The Dynamics of CD4+ T Cell Proliferation in Autopilot Model

Abstract

Under the assumption of the autopilot model, after antigen stimulation ex- ceeds a threshold, the proliferation and effector function of CD4+ T cells are self- sustained and do not need further antigen stimulation. However, CD4+ T cell pro- liferation is driven by their production of IL-2, which then binds to cells and triggers proliferation. Without regulation, this autocrine process forms a positive feedback loop that causes uncontrolled proliferation. This study mathematically modeled the regu- latory mechanisms of the CD4+ T cell response after infection, focusing on the role of IL-2 self-regulation and Treg in this mechanism. We performed a phase-space analysis to study the long-term behavior of the proliferation process. Our results show that IL-2 self-regulation alone is not sufficient to fully inhibit CD4+ T cell response, and that the involvement of Treg cells is essential to regulate the immune response effec- tively. In particular, when the rate of CD4+ T cell proliferation is controlled by the rate of IL-2-mediated CD4+ T cell removal, Treg cells control CD4+ T cell proliferation by releasing immunosuppressive cytokines such as IL-10 and TGF-β, thus inhibiting the unregulated immune response.

Keywords

Adaptive immune system / immune response / within-host / clonal expansion

References

[1] B. B. Au-Yeung, J. Zikherman, J. L. Mueller, J. F. Ashouri, M. Matloubian, D. A. Cheng, Y. Chen, K. M. Shokat, and A. Weiss, A sharp T-cell antigen receptor signaling threshold for T-cell proliferation, Proc. Natl. Acad. Sci. USA, 111:E3679-E3688, 2014.

[2] R. N. Bamford, A. J. Grant, J. D. Burton, C. Peters, G. Kurys, C. K. Goldman, J. Brennan, E. Roessler, and T. Waldmann, The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells, Proc. Natl. Acad. Sci. USA, 91:4940-4944, 1994.

[3] M. J. Bevan and P. J. Fink, The CD 8 response on autopilot, Nat. Immunol., 2:381-382, 2001.

[4] J. A. Bluestone and Q. Tang, Treg cells - the next frontier of cell therapy, Science, 362:154-155, 2018.

[5] W. Chen, TGF-β regulation of T cells, Annu. Rev. Immunol., 41:483-512, 2023.

[6] L. Cuesta-Herrera, L. Pastenes, A. D. Arencibia, F. Co´rdova-Lepe, and C. Montoya, Dynamics of activation and regulation of the immune response to attack by viral pathogens using mathematical modeling, Mathematics, 12:2681, 2024.

[7] K. Garc´ıa-Mart´ınez and K. Leo´n, Modeling the role of IL-2 in the interplay between CD4+ helper and regulatory T cells: Assessing general dynamical properties, J. Theor. Biol., 262:720-732, 2010.

[8] D. Gong and T. Malek, Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production, J. Immunol., 178:242-252, 2007.

[9] Z. Grossman and W. E. Paul, Adaptive cellular interactions in the immune system: The tunable activation threshold and the significance of subthreshold responses, Proc. Natl. Acad. Sci. USA, 89:10365-10369, 1992.

[10] H. Gudmundsdottir, A. D. Wells, and L. A. Turka, Dynamics and requirements of T cell clonal expansion in vivo at the single-cell level: Effector function is linked to proliferative capacity, J. Im-munol., 162:5212-5223, 1999.

[11] P. Hsu, B. Santner-Nanan, M. Hu, K. Skarratt, C. H. Lee, M. Stormon, M. Wong,S. J. Fuller, and R. Nanan, Il-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1, J. Immunol., 195:3665-3674, 2015.

[12] M. Huse, The T-cell-receptor signaling network, J. Cell Sci., 122:1269-1273, 2009.

[13] S. M. Kaech and R. Ahmed, Memory CD8+ T cell differentiation: Initial antigen encounter trig-gers a developmental program in naive cells, Nat. Immunol., 2:415-422, 2001.

[14] V. Kalia, S. Sarkar, S. Subramaniam, W. N. Haining,K. A. Smith, and R. Ahmed, Prolonged interleukin-2rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo, Immunity, 32:91-103, 2010.

[15] B. J. Kaskow and C. Baecher-Allan, Effector T cells in multiple sclerosis, Cold Spring Harb. Perspect. Med., 8(4):a029025, 2018.

[16] S. Khailaie, F. Bahrami, M. Janahmadi, P. Milanez-Almeida, J. Huehn, and M. Meyer-Hermann, A mathematical model of immune activation with a unified self-nonself concept, Front Immunol., 4:474, 2013.

[17] P. Khalili and R. Vatankhah, Studying the importance of regulatory T cells in chemoimmunother-apy mathematical modeling and proposing new approaches for developing a mathematical dynamic of cancer, J. Theor. Biol., 563:111437, 2023.

[18] T. R. Malek, The biology of interleukin-2, Annu. Rev. Immunol., 26:453-479, 2008.

[19] K. Murphy and C. Weaver, Janeway’s Immunobiology, Garland Science, 2016.

[20] B. H. Nelson, Il-2, regulatory T cells, and tolerance, J. Immunol., 172:3983-3988, 2004.

[21] L. V. Parijs and A. K. Abbas, Homeostasis and self-tolerance in the immune system: Turning lymphocytes off, Science, 280:243-248, 1998.

[22] S. Roy, M. Ren, S. Christensen, P. Li, R. Spolski, J. Phelan,L. Staudt, and W. J. Leonard, Blimp-1 is a negative regulator of IL-2 signaling in T cells, J. Immunol., 210(Supplement 1):243.01, 2023.

[23] A. H. Sharpe, Mechanisms of costimulation, Immunol. Rev., 229:5-11, 2009.

[24] M. J. van Stipdonk, E. E. Lemmens, and S. P. Schoenberger, Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation, Nat. Immunol., 2:423-429, 2001.

[25] Y. Wakabayashi et al., Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-Smad pathway, J. Biol. Chem., 286(41):35456—35465, 2011.

[26] M. Zhang, J. Ma,R. Edwards, and M. Li, The dynamics of CD4+ T cell proliferation and regula-tion, J. Biol. Dyn., 19:2458867, 2025.

[27] Y. Zhang,P. B. Alexander, and X.-F. Wang, TGF-β family signaling in the control of cell prolifer-ation and survival, Cold Spring Harb. Perspect. Biol., 9(4):a022145, 2017.

[28] J. Zhu,H. Yamane, and W. E. Paul, Differentiation of effector CD4 T cell populations, Annu. Rev. Immunol., 28:445-489, 2010.