The homeostasis and heterogeneity of regulatory T cells in sepsis

Abstract

Sepsis poses a critical threat to global health, mainly due to the disruption of immune homeostasis, which critically influences both early death and long-term adverse outcomes. Current evidence shows that regulatory T (Treg) cells-key mediators of adaptive immunity-play an essential role in maintaining immunological balance during sepsis progression. During the initial hyperinflammatory phase, Treg cells actively suppress excessive inflammation, reducing tissue damage. Paradoxically, in the subsequent immunosuppressive phase, expanded Treg populations may exacerbate immunosuppression by inhibiting effector cell function, ultimately leading to poorer clinical outcomes. Recent research has identified novel Treg-specific biomarkers in sepsis and explained how the septic environment affects Treg cell numbers and function through various signaling pathways. This review combines current understanding of the phenotypic features and roles of Treg cells in sepsis, examines the regulatory mechanisms controlling Treg dynamics within the inflammatory setting, and explores therapeutic strategies targeting Treg cells across different immune phases, emphasizing both existing challenges and future directions.

Keywords

Sepsis / regulatory T cell / Checkpoint / Immunotherapy

References

[1] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801-10. https://doi.org/10.1001/jama.2016.0287.

[2] Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395: 200-11. https://doi.org/10.1016/S0140-6736(19)32989-7.

[3] van der Poll T, Shankar-Hari M, Wiersinga WJ. The immunology of sepsis. Immunity 2021; 54: 2450-64. https://doi.org/10.1016/j.immuni.2021.10.012.

[4] Liu D, Huang SY, Sun JH, Zhang HC, Cai QL, Gao C, et al. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res 2022; 9: 56. https://doi.org/10.1186/s40779-022-00422-y.

[5] Venet F, Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol 2018; 14: 121-37. https://doi.org/10.1038/nrneph.2017.165.

[6] Gao YL, Yao Y, Zhang X, Chen F, Meng XL, Chen XS, et al. Regulatory T cells: angels or demons in the pathophysiology of sepsis? Front Immunol 2022; 13: 829210. https://doi.org/10.3389/fimmu.2022.829210.

[7] Daviaud F, Grimaldi D, Dechartres A, Charpentier J, Geri G, Marin N, et al. Timing and causes of death in septic shock. Ann Intensive Care 2015; 5: 16. https://doi.org/10.1186/s13613-015-0058-8.

[8] Martin-Loeches I, Singer M, Leone M. Sepsis: key insights, future directions, and immediate goals. A review and expert opinion. Intensive Care Med 2024; 50: 2043-9. https://doi.org/10.1007/s00134-024-07694-z.

[9] Savage PA, Klawon DEJ, Miller CH. Regulatory T cell development. Annu Rev Immunol 2020; 38: 421-53. https://doi.org/10.1146/annurev-immunol-100219-020937.

[10] Okeke EB, Okwor I, Mou Z, Jia P, Uzonna JE. CD4+CD25+ regulatory T cells attenuate lipopolysaccharide-induced systemic inflammatory responses and promotes survival in murine Escherichia coli infection. Shock 2013; 40: 65-73. https://doi.org/10.1097/SHK.0b013e318296e65b.

[11] Cavassani KA, Carson WF, Moreira AP, Wen H, Schaller MA, Ishii M, et al. The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood 2010; 115: 4403-11. https://doi.org/10.1182/blood-2009-09-241083.

[12] Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 1970; 18: 723-37.

[13] Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 2000; 101: 455-8. https://doi.org/10.1016/S0092-8674(00)80856-9.

[14] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-64. https://doi.org/10.4049/jimmunol.155.3.1151.

[15] Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999; 162: 5317-26. https://doi.org/10.4049/jimmunol.162.9.5317.

[16] Shevach EM. Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 2001; 193: F41-6. https://doi.org/10.1084/jem.193.11.F41.

[17] Sakaguchi S.Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22: 531-62. https://doi.org/10.1146/annurev.immunol.21.120601.141122.

[18] Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531-64. https://doi.org/10.1146/annurev.immunol.25.022106.141623.

[19] Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001; 27: 18-20. https://doi.org/10.1038/83707.

[20] Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20-1. https://doi.org/10.1038/83713.

[21] Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 2003; 15: 430-5. https://doi.org/10.1097/00002281-200307000-00010.

[22] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-6. https://doi.org/10.1038/ni904.

[23] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-61. https://doi.org/10.1126/science.1079490.

[24] Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003; 4: 337-42. https://doi.org/10.1038/ni909.

[25] Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007; 445: 766-70. https://doi.org/10.1038/nature05479.

[26] Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007; 8: 277-84. https://doi.org/10.1038/ni1437.

[27] Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T cells and human disease. Annu Rev Immunol 2020; 38: 541-66. https://doi.org/10.1146/annurev-immunol-042718-041717.

[28] Hori S. FOXP3 as a master regulator of T(reg) cells. Nat Rev Immunol 2021; 21: 618-9. https://doi.org/10.1038/s41577-021-00598-9.

[29] Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006; 203: 1701-11. https://doi.org/10.1084/jem.20060772.

[30] Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 2010; 184: 3433-41. https://doi.org/10.4049/jimmunol.0904028.

[31] Wegrzyn AS, Kedzierska AE, Obojski A. Identification and classification of distinct surface markers of T regulatory cells. Front Immunol 2022; 13: 1055805.

[32] Cao C, Ma T, Chai YF, Shou ST. The role of regulatory T cells in immune dysfunction during sepsis. World J Emerg Med 2015; 6: 5-9. https://doi.org/10.5847/wjem.j.1920-8642.2015.01.001.

[33] Kox WJ, Volk T, Kox SN, Volk HD. Immunomodulatory therapies in sepsis. Intensive Care Med 2000; 26 Suppl 1: S124-8. https://doi.org/10.1007/s001340051129.

[34] Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G.Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J Exp Med 2002; 196: 247-53. https://doi.org/10.1084/jem.20020642.

[35] Leng FY, Liu JL, Liu ZJ, Yin JY, Qu HP. Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during early-stage sepsis in ICU patients. J Microbiol Immunol Infect 2013; 46: 338-44. https://doi.org/10.1016/j.jmii.2012.06.012.

[36] Venet F, Chung CS, Kherouf H, Geeraert A, Malcus C, Poitevin F, et al. Increased circulating regulatory T cells (CD4(+)CD25(+)CD127(−)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med 2009; 35: 678-86. https://doi.org/10.1007/s00134-008-1337-8.

[37] Gupta DL, Bhoi S, Mohan T, Galwnkar S, Rao DN.Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with post traumatic sepsis. Cytokine 2016; 88: 214-21. https://doi.org/10.1016/j.cyto.2016.09.010.

[38] Hein F, Massin F, Cravoisy-Popovic A, Barraud D, Levy B, Bollaert PE, et al. The relationship between CD4+CD25+CD127-regulatory T cells and inflammatory response and outcome during shock states. Crit Care 2010; 14: R19. https://doi.org/10.1186/cc8876.

[39] Liu Q, An L, Qi Z, Zhao Y, Li C. Increased expression of programmed cell Death-1 in regulatory T cells of patients with severe sepsis and septic shock: An observational clinical study. Scand J Immunol 2017; 86: 408-17. https://doi.org/10.1111/sji.12612.

[40] Jiang W, Li X, Ding H, Wang K, Liu X, Wang Q, et al. PD-1 in Tregs predicts the survival in sepsis patients using sepsis-3 criteria: a prospective, two-stage study. Int Immunopharmacol 2020; 89: 107175. https://doi.org/10.1016/j.intimp.2020.107175.

[41] Carvelli J, Piperoglou C, Bourenne J, Farnarier C, Banzet N, Demerlé C, et al. Imbalance of circulating innate lymphoid cell subpopulations in patients with septic shock. Front Immunol 2019; 10: 2179. https://doi.org/10.3389/fimmu.2019.02179.

[42] Wu HP, Chung K, Lin CY, Jiang BY, Chuang DY, Liu YC. Associations of T helper 1, 2, 17 and regulatory T lymphocytes with mortality in severe sepsis. Inflamm Res 2013; 62: 751-63. https://doi.org/10.1007/s00011-013-0630-3.

[43] Kühlhorn F, Rath M, Schmoeckel K, Cziupka K, Nguyen HH, Hildebrandt P, et al. Foxp3+ regulatory T cells are required for recovery from severe sepsis. PLoS One 2013; 8: e65109. https://doi.org/10.1371/journal.pone.0065109.

[44] Pei F, Yao RQ, Ren C, Bahrami S, Billiar TR, Chaudry IH, et al. Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression. Mil Med Res 2022; 9: 74. https://doi.org/10.1186/s40779-022-00430-y.

[45] Monneret G, Debard AL, Venet F, Bohe J, Hequet O, Bienvenu J, et al. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med 2003; 31: 2068-71. https://doi.org/10.1097/01.CCM.0000069345.78884.0F.

[46] Lu X, Song CY, Wang P, Li L, Lin LY, Jiang S, et al. The clinical trajectory of peripheral blood immune cell subsets, T-cell activation, and cytokines in septic patients. Inflamm Res 2024; 73: 145-55. https://doi.org/10.1007/s00011-023-01825-w.

[47] Chen K, Zhou QX, Shan HW, Li WF, Lin ZF. Prognostic value of CD4(+)CD25(+) Tregs as a valuable biomarker for patients with sepsis in ICU. World J Emerg Med 2015; 6: 40-3. https://doi.org/10.5847/wjem.j.1920-8642.2015.01.007.

[48] Liu Q, Lu Y, An L, Li CS. B-and T-lymphocyte attenuator expression on regulatory T-cells in patients with severe sepsis. Chin Med J 2018; 131: 2637-9. https://doi.org/10.4103/0366-6999.244104.

[49] Alhamdan F, Koutsogiannaki S, Yuki K. The landscape of immune dysregulation in pediatric sepsis at a single-cell resolution. Clin Immunol 2024; 262: 110175. https://doi.org/10.1016/j.clim.2024.110175.

[50] Yin F, Xi YL, Wang Y, Li BR, Qian J, Ren H, et al. The clinical outcomes and biomarker features of severe sepsis/septic shock with severe neutropenia: a retrospective cohort study. Transl Pediatr 2021; 10: 464-73. https://doi.org/10.21037/tp-20-230.

[51] Huang LF, Yao YM, Dong N, Yu Y, He LX, Sheng ZY. Association between regulatory T cell activity and sepsis and outcome of severely burned patients: a prospective, observational study. Crit Care 2010; 14: R3. https://doi.org/10.1186/cc8232.

[52] Venet F, Pachot A, Debard AL, Bohé J, Bienvenu J, Lepape A, et al. Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25-lymphocytes. Crit Care Med 2004; 32: 2329-31. https://doi.org/10.1097/01.CCM.0000145999.42971.4B.

[53] He W, Xiao K, Fang M, Xie L. Immune cell number, phenotype, and function in the elderly with sepsis. Aging Dis 2021; 12: 277-96. https://doi.org/10.14336/AD.2020.0627.

[54] Li J, Li M, Su L, Wang H, Xiao K, Deng J, et al. Alterations of T helper lymphocyte subpopulations in sepsis, severe sepsis, and septic shock: a prospective observational study. Inflammation 2015; 38: 995-1002. https://doi.org/10.1007/s10753-014-0063-3.

[55] Nascimento DC, Melo PH, Piñeros AR, Ferreira RG, Colón DF, Donate PB, et al. IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population. Nat Commun 2017; 8: 14919. https://doi.org/10.1038/ncomms14919.

[56] Huang S, Liu D, Han L, Deng J, Wang Z, Jiang J, et al. Decoding the potential role of regulatory T cells in sepsis-induced immunosuppression. Eur J Immunol 2024; 54: e2350730.

[57] Zhang T, Yu-Jing L, Ma T. The immunomodulatory function of adenosine in sepsis. Front Immunol 2022; 13: 936547. https://doi.org/10.3389/fimmu.2022.936547.

[58] Zhang YT, Xing ML, Fang HH, Li WD, Wu L, Chen ZP. Effects of lactate on metabolism and differentiation of CD4(+)T cells. Mol Immunol 2023; 154: 96-107. https://doi.org/10.1016/j.molimm.2022.12.015.

[59] Liao C, Luo S, Liu X, Zhang L, Xie P, Zhou W, et al. Siglec-F(+) neutrophils in the spleen induce immunosuppression following acute infection. Theranostics 2024; 14: 2589-604. https://doi.org/10.7150/thno.93812.

[60] Shi Y, Wu D, Wang Y, Shao Y, Zeng F, Zhou D, et al. Treg and neutrophil extracellular trap interaction contributes to the development of immunosuppression in sepsis. JCI Insight 2024; 9:e180132. https://doi.org/10.1172/jci.insight.180132.

[61] Zhou M, Fang H, Du M, Li C, Tang R, Liu H, et al. The modulation of regulatory T cells via HMGB1/PTEN/beta-catenin Axis in LPS induced acute lung injury. Front Immunol 2019; 10: 1612. https://doi.org/10.3389/fimmu.2019.01612.

[62] Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev 2014; 259: 88-102. https://doi.org/10.1111/imr.12160.

[63] Russler-Germain EV, Rengarajan S, Hsieh CS. Antigen-specific regulatory T-cell responses to intestinal microbiota. Mucosal Immunol 2017; 10: 1375-86. https://doi.org/10.1038/mi.2017.65.

[64] Yang WY, Shao Y, Lopez-Pastrana J, Mai J, Wang H, Yang XF. Pathological conditions re-shape physiological Tregs into pathological Tregs. Burns Trauma 2015; 3: 1. https://doi.org/10.1186/s41038-015-0001-0.

[65] van der Veeken J, Campbell C, Pritykin Y, Schizas M, Verter J, Hu W, et al. Genetic tracing reveals transcription factor Foxp3-dependent and Foxp3-independent functionality of peripherally induced Treg cells. Immunity 2022; 55: 1173-1184.e7. https://doi.org/10.1016/j.immuni.2022.05.010.

[66] Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced regulatory T cells: their development, stability, and applications. Trends Immunol 2016; 37: 803-11. https://doi.org/10.1016/j.it.2016.08.012.

[67] Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 2012; 119: 4430-40. https://doi.org/10.1182/blood-2011-11-392324.

[68] Hoeppli RE, MacDonald KN, Leclair P, Fung VCW, Mojibian M, Gillies J, et al. Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions. Am J Transplant 2019; 19: 62-76. https://doi.org/10.1111/ajt.14936.

[69] Drechsler S, Zipperle J, Rademann P, Jafarmadar M, Klotz A, Bahrami S, et al. Splenectomy modulates early immunoinflammatory responses to trauma-hemorrhage and protects mice against secondary sepsis. Sci Rep 2018; 8: 14890. https://doi.org/10.1038/s41598-018-33232-1.

[70] Gao DN, Yang ZX, Qi QH. Roles of PD-1, Tim-3 and CTLA-4 in immunoregulation in regulatory T cells among patients with sepsis. Int J Clin Exp Med 2015; 8: 18998-9005.

[71] Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010; 236: 219-42. https://doi.org/10.1111/j.1600-065X.2010.00923.x.

[72] Cai J, Wang D, Zhang G, Guo X. The role of PD-1/PD-L1 Axis In Treg development and function: implications for cancer immunotherapy. Onco Targets Ther 2019;Volume 12: 8437-45. https://doi.org/10.2147/OTT.S221340.

[73] Tang L, Bai J, Chung CS, Lomas-Neira J, Chen Y, Huang X, et al. Programmed cell death receptor ligand 1 modulates the regulatory T cells’ capacity to repress shock/sepsis-induced indirect acute lung injury by recruiting phosphatase SRC homology region 2 domain-containing phosphatase 1. Shock 2015; 43: 47-54. https://doi.org/10.1097/SHK.0000000000000247.

[74] Tang L, Bai J, Chung CS, Lomas-Neira J, Chen Y, Huang X, et al. Active players in resolution of shock/sepsis induced indirect lung injury: immunomodulatory effects of Tregs and PD-1. J Leukoc Biol 2014; 96: 809-20. https://doi.org/10.1189/jlb.4MA1213-647RR.

[75] Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol 2023; 14: 1198365. https://doi.org/10.3389/fimmu.2023.1198365.

[76] Tekguc M, Wing JB, Osaki M, Long J, Sakaguchi S. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells. Proc Natl Acad Sci USA 2021; 118:e2023739118. https://doi.org/10.1073/pnas.2023739118.

[77] Wang L, Zhang Z, Chen X, Yu F, Huang H, Shen X, et al. Relationship between the expression of PD-1 and CTLA-4 on T lymphocytes and the severity and prognosis of sepsis. Int J Gen Med 2023; 16: 1513-25. https://doi.org/10.2147/IJGM.S402586.

[78] McBride MA, Patil TK, Bohannon JK, Hernandez A, Sherwood ER, Patil NK. Immune checkpoints: novel therapeutic targets to attenuate sepsis-induced immunosuppression. Front Immunol 2020; 11: 624272. https://doi.org/10.3389/fimmu.2020.624272.

[79] Shubin NJ, Monaghan SF, Heffernan DS, Chung CS, Ayala A. B and T lymphocyte attenuator expression on CD4+ T-cells associates with sepsis and subsequent infections in ICU patients. Crit Care 2013; 17: R276. https://doi.org/10.1186/cc13131.

[80] Gupta S, Thornley TB, Gao W, Larocca R, Turka LA, Kuchroo VK, et al. Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs. J Clin Invest 2012; 122: 2395-404. https://doi.org/10.1172/JCI45138.

[81] Sakuishi K, Ngiow SF, Sullivan JM, Teng MW, Kuchroo VK, Smyth MJ, et al. TIM3(+)FOXP3(+) regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Onco Targets Ther 2013; 2: e23849.

[82] Gautron AS, Dominguez-Villar M, de Marcken M, Hafler DA. Enhanced suppressor function of TIM-3+FoxP3+ regulatory T cells. Eur J Immunol 2014; 44: 2703-11. https://doi.org/10.1002/eji.201344392.

[83] Moorman JP, Wang JM, Zhang Y, Ji XJ, Ma CJ, Wu XY, et al. Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection. J Immunol 2012; 189: 755-66. https://doi.org/10.4049/jimmunol.1200162.

[84] Liu X, Jiang S, Zhang Q, Xu S, Bao X, Cao W, et al. Tim-3 regulates Tregs’ ability to resolve the inflammation and proliferation of acute lung injury by modulating macrophages polarization. Shock 2018; 50: 455-64. https://doi.org/10.1097/SHK.0000000000001070.

[85] Deuss FA, Gully BS, Rossjohn J, Berry R. Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT). J Biol Chem 2017; 292: 11413-22. https://doi.org/10.1074/jbc.M117.786483.

[86] Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26: 923-37. https://doi.org/10.1016/j.ccell.2014.10.018.

[87] Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 2014; 40: 569-81. https://doi.org/10.1016/j.immuni.2014.02.012.

[88] Lucca LE, Axisa PP, Singer ER, Nolan NM, Dominguez-Villar M, Hafler DA. TIGIT signaling restores suppressor function of Th1 Tregs. JCI Insight 2019; 4: e124427. https://doi.org/10.1172/jci.insight.124427.

[89] Lee DJ. The relationship between TIGIT(+) regulatory T cells and autoimmune disease. Int Immunopharmacol 2020; 83: 106378. https://doi.org/10.1016/j.intimp.2020.106378.

[90] Zhang Y, Maksimovic J, Naselli G, Qian J, Chopin M, Blewitt ME, et al. Genome-wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood 2013; 122: 2823-36. https://doi.org/10.1182/blood-2013-02-481788.

[91] de Lima MHF, Hiroki CH, de Fatima BV, Cebinelli GCM, Santos J, Rosa MH, et al. Sepsis-induced immunosuppression is marked by an expansion of a highly suppressive repertoire of FOXP3+ T-regulatory cells expressing TIGIT. J Infect Dis 2022; 225: 531-41. https://doi.org/10.1093/infdis/jiab405.

[92] Liu YC, Shou ST, Chai YF. Immune checkpoints in sepsis: new hopes and challenges. Int Rev Immunol 2022; 41: 207-16. https://doi.org/10.1080/08830185.2021.1884247.

[93] Webb GJ, Hirschfield GM, Lane PJ. OX40, OX40L and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol 2016; 50: 312-32. https://doi.org/10.1007/s12016-015-8498-3.

[94] Ruby CE, Yates MA, Hirschhorn-Cymerman D, Chlebeck P, Wolchok JD, Houghton AN, et al. Cutting edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. J Immunol 2009; 183: 4853-7. https://doi.org/10.4049/jimmunol.0901112.

[95] Xiao X, Gong W, Demirci G, Liu W, Spoerl S, Chu X, et al. New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol 2012; 188: 892-901. https://doi.org/10.4049/jimmunol.1101373.

[96] Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood 2007; 110: 2501-10. https://doi.org/10.1182/blood-2007-01-070748.

[97] Lu Y, An L, Liu Q, Li C. Expression and clinical correlations of costimulatory molecules on peripheral T lymphocyte subsets of early-stage severe sepsis: a prospective observational study. Shock 2018; 49: 631-40. https://doi.org/10.1097/SHK.0000000000001017.

[98] Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 2013; 501: 252-6. https://doi.org/10.1038/nature12428.

[99] Xu J, Li X, Yuan Q, Wang C, Xu L, Wei X, et al. The semaphorin 4A-neuropilin 1 axis alleviates kidney ischemia reperfusion injury by promoting the stability and function of regulatory T cells. Kidney Int 2021; 100: 1268-81. https://doi.org/10.1016/j.kint.2021.08.023.

[100] Gao Y, Zhang X, Wang Z, Qiu Y, Liu Y, Shou S, et al. The contribution of neuropilin-1 in the stability of CD4(+)CD25(+) regulatory T cells through the TGF-β1/Smads signaling pathway in the presence of lipopolysaccharides. Immun Inflamm Dis 2022; 10: 143-54. https://doi.org/10.1002/iid3.551.

[101] Gao YL, Wang CX, Wang ZY, Li WJ, Liu YC, Shou ST, et al. Targeting Neuropilin-1 suppresses the stability of CD4(+)CD25(+) regulatory T cells via the NF-κB Signaling pathway in sepsis. Infect Immun 2021; 89: e00399-20.

[102] Glinka Y, Prud’homme GJ. Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 2008; 84: 302-10. https://doi.org/10.1189/jlb.0208090.

[103] Glinka Y, Stoilova S, Mohammed N, Prud’homme GJ. Neuropilin-1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-beta. Carcinogenesis 2011; 32: 613-21.

[104] Mizumoto N, Kumamoto T, Robson SC, Sévigny J, Matsue H, Enjyoji K, et al. CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med 2002; 8: 358-65. https://doi.org/10.1038/nm0402-358.

[105] Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007; 110: 1225-32. https://doi.org/10.1182/blood-2006-12-064527.

[106] Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J Immunol 2006; 177: 6780-6. https://doi.org/10.4049/jimmunol.177.10.6780.

[107] Huang H, Xu R, Lin F, Bao C, Wang S, Ji C, et al. High circulating CD39(+) regulatory T cells predict poor survival for sepsis patients. Int J Infect Dis 2015; 30: 57-63. https://doi.org/10.1016/j.ijid.2014.11.006.

[108] Bao R, Shui X, Hou J, Li J, Deng X, Zhu X, et al. Adenosine and the adenosine A2A receptor agonist, CGS21680, upregulate CD39 and CD73 expression through E2F-1 and CREB in regulatory T cells isolated from septic mice. Int J Mol Med 2016; 38: 969-75. https://doi.org/10.3892/ijmm.2016.2679.

[109] Kumar V. Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute lung injury. Front Immunol 2020; 11: 1722. https://doi.org/10.3389/fimmu.2020.01722.

[110] Xia H, Wang F, Wang M, Wang J, Sun S, Chen M, et al. Maresin1 ameliorates acute lung injury induced by sepsis through regulating Th17/Treg balance. Life Sci 2020; 254: 117773. https://doi.org/10.1016/j.lfs.2020.117773.

[111] Zhao J, Liu Y, Hu JN, Peng M, Dong N, Zhu XM, et al. Autocrine regulation of Interleukin-3 in the activity of regulatory T cells and its effectiveness in the pathophysiology of sepsis. J Infect Dis 2021; 223: 893-904. https://doi.org/10.1093/infdis/jiaa441.

[112] Xu R, Jacques LC, Khandaker S, Beentjes D, Leon-Rios M, Wei X, et al. TNFR2(+) regulatory T cells protect against bacteremic pneumococcal pneumonia by suppressing IL-17A-producing γδ T cells in the lung. Cell Rep 2023; 42: 112054. https://doi.org/10.1016/j.celrep.2023.112054.

[113] Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int 2019; 96: 1083-99. https://doi.org/10.1016/j.kint.2019.05.026.

[114] Zhou X, Yao J, Lin J, Liu J, Dong L, Duan M. Th17/regulatory T-cell imbalance and acute kidney injury in patients with sepsis. J Clin Med 2022; 11: 4027. https://doi.org/10.3390/jcm11144027.

[115] do Valle Duraes F, Lafont A, Beibel M, Martin K, Darribat K, Cuttat R, et al. Immune cell landscaping reveals a protective role for regulatory T cells during kidney injury and fibrosis. JCI Insight 2020; 5:e130651.

[116] Chung HY, Wickel J, Brunkhorst FM, Geis C. Sepsis-associated encephalopathy: from delirium to dementia? J Clin Med 2020; 9: 703. https://doi.org/10.3390/jcm9030703.

[117] Ren C, Yao RQ, Zhang H, Feng YW, Yao YM. Sepsis-associated encephalopathy: a vicious cycle of immunosuppression. J Neuroinflammation 2020; 17: 14. https://doi.org/10.1186/s12974-020-1701-3.

[118] Sonneville R, de Montmollin E, Poujade J, Garrouste-Orgeas M, Souweine B, Darmon M, et al. Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med 2017; 43: 1075-84. https://doi.org/10.1007/s00134-017-4807-z.

[119] Saito M, Fujinami Y, Ono Y, Ohyama S, Fujioka K, Yamashita K, et al. Infiltrated regulatory T cells and Th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis. Brain Behav Immun 2021; 92: 25-38. https://doi.org/10.1016/j.bbi.2020.11.010.

[120] Chang CL, Chen HH, Chen KH, Chiang JY, Li YC, Lin HS, et al. Adipose-derived mesenchymal stem cell-derived exosomes markedly protected the brain against sepsis syndrome induced injury in rat. Am J Transl Res 2019; 11: 3955-71.

[121] Strnad P, Tacke F, Koch A, Trautwein C. Liver-guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol 2017; 14: 55-66. https://doi.org/10.1038/nrgastro.2016.168.

[122] Yeh CL, Tanuseputero SA, Wu JM, Tseng YR, Yang PJ, Lee PC, et al. Intravenous arginine administration benefits CD4(+) T-cell homeostasis and attenuates liver inflammation in mice with polymicrobial sepsis. Nutrients 2020; 12: 1047. https://doi.org/10.3390/nu12041047.

[123] Gray CC, Biron-Girard B, Wakeley ME, Chung CS, Chen Y, Quiles-Ramirez Y, et al. Negative immune checkpoint protein, VISTA, regulates the CD4(+)T(reg) population during sepsis progression to promote acute sepsis recovery and survival. Front Immunol 2022; 13: 861670. https://doi.org/10.3389/fimmu.2022.861670.

[124] Wang P, Shi B, Wang C, Wang Y, Que W, Jiang Z, et al. Hepatic pannexin-1 mediates ST2(+) regulatory T cells promoting resolution of inflammation in lipopolysaccharide-induced endotoxemia. Clin Transl Med 2022; 12: e849. https://doi.org/10.1002/ctm2.849.

[125] Huo R, Wang L, Wang X, Zhao Y, Wang Y, Zhao X, et al. Removal of regulatory T cells prevents secondary chronic infection but increases the mortality of subsequent sub-acute infection in sepsis mice. Oncotarget 2016; 7: 10962-75. https://doi.org/10.18632/oncotarget.7682.

[126] Huppert LA, Green MD, Kim L, Chow C, Leyfman Y, Daud AI, et al. Tissue-specific Tregs in cancer metastasis: opportunities for precision immunotherapy. Cell Mol Immunol 2022; 19: 33-45. https://doi.org/10.1038/s41423-021-00742-4.

[127] Hu ZQ, Yao YM, Chen W, Bian JL, Zhao LJ, Chen LW, et al. Partial depletion of regulatory T cells enhances host inflammatory response against acute Pseudomonas aeruginosa infection after sepsis. Inflammation 2018; 41: 1780-90. https://doi.org/10.1007/s10753-018-0821-8.

[128] Nemeth ZH, Csoka B, Wilmanski J, Xu D, Lu Q, Ledent C, et al. Adenosine A2A receptor inactivation increases survival in polymicrobial sepsis. J Immunol 2006; 176: 5616-26. https://doi.org/10.4049/jimmunol.176.9.5616.

[129] Bao R, Hou J, Li Y, Bian J, Deng X, Zhu X, et al. Adenosine promotes Foxp3 expression in Treg cells in sepsis model by activating JNK/AP-1 pathway. Am J Transl Res 2016; 8: 2284-92.

[130] Zhang T, Fu W, Liu D, He Y, Wang J, Ma T. Adenosine influences Foxp3 expression of Tregs via the A2ar/Creb pathway in a mouse model of sepsis. Shock 2024; 61: 924-33.

[131] Zhang T, Zhao J, Zheng T, Fu W, Ma T. Adenosine 2A receptor antagonists promote lymphocyte proliferation in sepsis by inhibiting Treg expression of PD-L1 in spleen. Immunology 2024; 171: 566-82. https://doi.org/10.1111/imm.13744.

[132] Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022; 40: 201-218.e9. https://doi.org/10.1016/j.ccell.2022.01.001.

[133] Ding R, Yu X, Hu Z, Dong Y, Huang H, Zhang Y, et al. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells. Immunity 2024; 57: 528-540.e6. https://doi.org/10.1016/j.immuni.2024.01.019.

[134] Gu J, Zhou J, Chen Q, Xu X, Gao J, Li X, et al. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep 2022; 39: 110986. https://doi.org/10.1016/j.celrep.2022.110986.

[135] Zhou J, Gu J, Qian Q, Zhang Y, Huang T, Li X, et al. Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria. J Clin Invest 2024; 134: e175897. https://doi.org/10.1172/JCI175897.

[136] Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 2021; 591: 645-51. https://doi.org/10.1038/s41586-020-03045-2.

[137] Kim YS, Jeong YS, Bae GH, Kang JH, Lee M, Zabel BA, et al. CD200R(high) neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T cells. Cell Mol Immunol 2024; 21: 349-61. https://doi.org/10.1038/s41423-024-01136-y.

[138] Zhang H, Wang Y, Qu M, Li W, Wu D, Cata JP, et al. Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis. Clin Transl Med 2023; 13:e1170. https://doi.org/10.1002/ctm2.1170.

[139] Kumar S, Payal N, Srivastava VK, Kaushik S, Saxena J, Jyoti A. Neutrophil extracellular traps and organ dysfunction in sepsis. Clin Chim Acta 2021; 523: 152-62. https://doi.org/10.1016/j.cca.2021.09.012.

[140] Wang H, Zhang H, Wang Y, Brown ZJ, Xia Y, Huang Z, et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J Hepatol 2021; 75: 1271-83. https://doi.org/10.1016/j.jhep.2021.07.032.

[141] Chen Y, Wang L, Liu M, Zhao J, Xu X, Wei D, et al. Mechanism of exosomes from adipose-derived mesenchymal stem cells on sepsis-induced acute lung injury by promoting TGF-beta secretion in macrophages. Surgery 2023; 174: 1208-19. https://doi.org/10.1016/j.surg.2023.06.017.

[142] Zheng LY, Duan Y, He PY, Wu MY, Wei ST, Du XH, et al. Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death. Cell Mol Biol Lett 2024; 29: 81. https://doi.org/10.1186/s11658-024-00602-9.

[143] Kushwah R, Wu J, Oliver JR, Jiang G, Zhang J, Siminovitch KA, et al. Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg. Eur J Immunol 2010; 40: 1022-35. https://doi.org/10.1002/eji.200939782.

[144] Barnes MJ, Li CM, Xu Y, An J, Huang Y, Cyster JG. The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function. J Exp Med 2015; 212: 1011-20. https://doi.org/10.1084/jem.20141827.

[145] Qiu D, Chu X, Hua L, Yang Y, Li K, Han Y, et al. Gpr174-deficient regulatory T cells decrease cytokine storm in septic mice. Cell Death Dis 2019; 10: 233. https://doi.org/10.1038/s41419-019-1462-z.

[146] Yue X, Lio CJ, Samaniego-Castruita D, Li X, Rao A. Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nat Commun 2019; 10: 2011. https://doi.org/10.1038/s41467-019-09541-y.

[147] Nakatsukasa H, Oda M, Yin J, Chikuma S, Ito M, Koga-Iizuka M, et al. Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression. Int Immunol 2019; 31: 335-47. https://doi.org/10.1093/intimm/dxz008.

[148] Wu Q, Carlos AR, Braza F, Bergman ML, Kitoko JZ, Bastos-Amador P, et al. Ferritin heavy chain supports stability and function of the regulatory T cell lineage. EMBO J 2024; 43: 1445-83. https://doi.org/10.1038/s44318-024-00064-x.

[149] Zhang H, Wu T, Ren C, Dong N, Wu Y, Yao Y. p53 promotes the expansion of regulatory T cells via DNMT3a-and TET2-mediated Foxp3 expression in sepsis. Burns Trauma 2023; 11: tkad021.

[150] Durand M, Hagimont E, Louis H, Asfar P, Frippiat JP, Singer M, et al. The β1-adrenergic receptor contributes to sepsis-induced immunosuppression through modulation of regulatory T-cell inhibitory function. Crit Care Med 2022; 50: e707-18. https://doi.org/10.1097/CCM.0000000000005503.

[151] Wu Z, Liu X, Huang W, Chen J, Li S, Chao J, et al. CIRP increases Foxp3(+) regulatory T cells and inhibits development of Th17 cells by enhancing TLR4-IL-2 signaling in the late phase of sepsis. Int Immunopharmacol 2024; 132: 111924. https://doi.org/10.1016/j.intimp.2024.111924.

[152] Li L, Lu YQ. The regulatory role of high-mobility group protein 1 in sepsis-related immunity. Front Immunol 2020; 11: 601815. https://doi.org/10.3389/fimmu.2020.601815.

[153] Zhou M, Zhang Y, Tang R, Liu H, Du M, Gao Z, et al. HMGB1/TLR4 Signaling affects regulatory T cells in acute lung injury. J Inflamm Res 2021; 14: 1551-61. https://doi.org/10.2147/JIR.S302967.

[154] Yuan Y, Yan D, Han G, Gu G, Ren J. Complement C3 depletion links to the expansion of regulatory T cells and compromises T-cell immunity in human abdominal sepsis: a prospective pilot study. J Crit Care 2013; 28: 1032-8. https://doi.org/10.1016/j.jcrc.2013.09.007.

[155] Chen X, Chen X, Yang Y, Luo N, Yang J, Zhong L, et al. Protective role of the novel cytokine Metrnl/interleukin-41 in host immunity defense during sepsis by promoting macrophage recruitment and modulating Treg/Th17 immune cell balance. Clin Immunol 2023; 254: 109690. https://doi.org/10.1016/j.clim.2023.109690.

[156] Slim MA, van Mourik N, Bakkerus L, Fuller K, Acharya L, Giannidis T, et al. Towards personalized medicine: a scoping review of immunotherapy in sepsis. Crit Care 2024; 28: 183. https://doi.org/10.1186/s13054-024-04964-6.

[157] Zhang S, Shan J, Jie Y, Zhang X, Zhu M, Shen J, et al. Inhibition of PI3K p110delta rebalanced Th17/Treg and reduced macrophages pyroptosis in LPS-induced sepsis. Mol Immunol 2024; 170: 110-8. https://doi.org/10.1016/j.molimm.2024.04.008.

[158] Nadeem A, Al-Harbi NO, Ahmad SF, Al-Harbi MM, Alhamed AS, Alfardan AS, et al. Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress. Int Immunopharmacol 2020; 83: 106369. https://doi.org/10.1016/j.intimp.2020.106369.

[159] Xiong W, Xia J, Peng X, Tan Y, Chen W, Zhou M, et al. Novel therapeutic role of Ganoderma polysaccharides in a septic mouse model-the key role of macrophages. Heliyon 2024; 10: e26732. https://doi.org/10.1016/j.heliyon.2024.e26732.

[160] Chen L, Liu X, Wang X, Lu Z, Ye Y. Berberine alleviates acute lung injury in septic mice by modulating Treg/Th17 homeostasis and downregulating NF-kappaB Signaling. Drug Des Devel Ther 2023; 17: 1139-51. https://doi.org/10.2147/DDDT.S401293.

[161] Koprivica I, Gajic D, Pejnovic N, Paunovic V, Saksida T, Stojanovic I. Ethyl pyruvate promotes proliferation of regulatory T cells by increasing glycolysis. Molecules 2020; 25: 4112. https://doi.org/10.3390/molecules25184112.

[162] Heuer JG, Zhang T, Zhao J, Ding C, Cramer M, Justen KL, et al. Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol 2005; 174: 7141-6. https://doi.org/10.4049/jimmunol.174.11.7141.

[163] Song H, Zhou Y, Li G, Bai J. Regulatory T cells contribute to the recovery of acute lung injury by upregulating Tim-3. Inflammation 2015; 38: 1267-72. https://doi.org/10.1007/s10753-014-0096-7.

[164] Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009; 58: 929-39. https://doi.org/10.1136/gut.2008.168534.

[165] Chao YH, Wu HP, Wu KH, Tsai YG, Peng CT, Lin KC, et al. An increase in CD3+CD4+CD25+ regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis. PLoS One 2014; 9: e110338. https://doi.org/10.1371/journal.pone.0110338.

[166] Parolini O, Souza-Moreira L, O’Valle F, Magatti M, Hernandez-Cortes P, Gonzalez-Rey E, et al. Therapeutic effect of human amniotic membrane-derived cells on experimental arthritis and other inflammatory disorders. Arthritis Rheumatol 2014; 66: 327-39. https://doi.org/10.1002/art.38206.

[167] Zhuxiao R, Shuo Y, Jiangxue H, Jingjun P, Qi Z, Zhu W, et al. Antimicrobial peptide LL37 and regulatory T cell associated with late-onset sepsis in very preterm infants. iScience 2024; 27: 109780. https://doi.org/10.1016/j.isci.2024.109780.

[168] Lin M, Lei S, Chai Y, Xu J, Wang Y, Wu C, et al. Immunosuppressive microvesicles-mimetic derived from tolerant dendritic cells to target T-lymphocytes for inflammation diseases therapy. J Nanobiotechnology 2024; 22: 201. https://doi.org/10.1186/s12951-024-02470-z.

[169] Sun L, Fang K, Yang Z. Combination therapy with probiotics and anti-PD-L1 antibody synergistically ameliorates sepsis in mouse model. Heliyon 2024; 10: e31747. https://doi.org/10.1016/j.heliyon.2024.e31747.

[170] Hotchkiss RS, Colston E, Yende S, Angus DC, Moldawer LL, Crouser ED, et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized, placebo-controlled, single ascending dose study of Antiprogrammed cell death-ligand 1 antibody (BMS-936559). Crit Care Med 2019; 47: 632-42. https://doi.org/10.1097/CCM.0000000000003685.

[171] Patil NK, Guo Y, Luan L, Sherwood ER. Targeting immune cell checkpoints during sepsis. Int J Mol Sci 2017; 18: 2413. https://doi.org/10.3390/ijms18112413.

[172] Hiraki S, Ono S, Tsujimoto H, Kinoshita M, Takahata R, Miyazaki H, et al. Neutralization of interleukin-10 or transforming growth factor-β decreases the percentages of CD4+CD25+Foxp3+ regulatory T cells in septic mice, thereby leading to an improved survival. Surgery 2012; 151: 313-22. https://doi.org/10.1016/j.surg.2011.07.019.

[173] Zhao GJ, Lu ZQ, Tang LM, Wu ZS, Wang DW, Zheng JY, et al. Curcumin inhibits suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. Int Immunopharmacol 2012; 14: 99-106. https://doi.org/10.1016/j.intimp.2012.06.016.

[174] Zheng YS, Wu ZS, Ni HB, Ke L, Tong ZH, Li WQ, et al. Codonopsis pilosula polysaccharide attenuates cecal ligation and puncture sepsis via circuiting regulatory T cells in mice. Shock 2014; 41: 250-5. https://doi.org/10.1097/SHK.0000000000000091.

[175] Hou YC, Wu JM, Wang MY, Wu MH, Chen KY, Yeh SL, et al. Modulatory effects of astragalus polysaccharides on T-cell polarization in mice with polymicrobial sepsis. Mediat Inflamm 2015; 2015: 826319. https://doi.org/10.1155/2015/826319.

[176] Zhao GJ, Yang XY, Zhang C, Dong W, Dong FB, Zhang J, et al. Supplementation WITH NICOTINAMIDE RIBOSIDE ATTENUATES T CELL EXHAUSTION AND IMPROVES SURVIVAL IN SEPSIS. Shock 2023; 60: 238-47. https://doi.org/10.1097/SHK.0000000000002153.

[177] Chen J, He X, Bai Y, Liu J, Wong YK, Xie L, et al. Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis. J Pharm Anal 2023; 13: 817-29. https://doi.org/10.1016/j.jpha.2023.02.006.

[178] Ono S, Kimura A, Hiraki S, Takahata R, Tsujimoto H, Kinoshita M, et al. Removal of increased circulating CD4+CD25+Foxp3+ regulatory T cells in patients with septic shock using hemoperfusion with polymyxin B-immobilized fibers. Surgery 2013; 153: 262-71. https://doi.org/10.1016/j.surg.2012.06.023.

[179] Shoji H, Opal SM. Therapeutic rationale for endotoxin removal with polymyxin B immobilized Fiber column (PMX) for septic shock. Int J Mol Sci 2021; 22: 2228. https://doi.org/10.3390/ijms22042228.

[180] Wang HW, Yang W, Gao L, Kang JR, Qin JJ, Liu YP, et al. Adoptive transfer of bone marrow-derived dendritic cells decreases inhibitory and regulatory T-cell differentiation and improves survival in murine polymicrobial sepsis. Immunology 2015; 145: 50-9. https://doi.org/10.1111/imm.12423.

[181] Cajander S, Kox M, Scicluna BP, Weigand MA, Mora RA, Flohé SB, et al. Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine. Lancet Respir Med 2024; 12: 305-22. https://doi.org/10.1016/S2213-2600(23)00330-2.