The mucosal immune system in the oral cavity—an orchestra of T cell diversity

Abstract

The diverse immune responses provided by T cells in the lining of the oral cavity have been reviewed by US and Chinese researchers. The oral-pharyngeal cavity is the gateway to the gastrointestinal (GI) and respiratory tracts, and is exposed to microbes, food particles and other substances. The oral mucosal layers contain many different types of T cells that protect against infection but detailed knowledge of their function is limited. WanJun Chen, Qian-Ming Chen and co-workers at the National Institutes of Health in Maryland, and Sichuan University in Chengdu, base their review on the more established knowledge of the GI mucosal system. They find that the oral cavity lining has many similar functions to the lining of the GI but produces some unique signalling proteins. The authors highlight the need for more research into this important immune barrier.

Keywords

mucosal immune system / oral-pharyngeal mucosa / T cell

References

[1] Murphy KP. Janeway’s immunobiology, 2011 London/New York 465-466.

[2] van Wijk F, Cheroutre H. Intestinal T cells: facing the mucosal immune dilemma with synergy and diversity. Semin Immunol, 2009, 21(3): 130-138.

[3] Dobbins WO 3rd. Human intestinal intraepithelial lymphocytes. Gut, 1986, 27(8): 972-985.

[4] van Wijk F, Cheroutre H. Mucosal T cells in gut homeostasis and inflammation. Expert Rev Clin Immunol, 2010, 6(4): 559-566.

[5] Konkel JE, Chen W. Balancing acts: the role of TGF-β in the mucosal immune system. Trends Mol Med, 2011, 17(11): 668-676.

[6] O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4⁺ T cells. Science, 2010, 327(5969): 1098-1102.

[7] Zhou L, Chong MM, Littman DR. Plasticity of CD4⁺ T cell lineage differentiation. Immunity, 2009, 30(5): 646-655.

[8] Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature, 1996, 383(6603): 787-793.

[9] Ma CS, Deenick EK, Batten M. The origins, function, and regulation of T follicular helper cells. J Exp Med, 2012, 209(7): 1241-1253.

[10] Amsen D, Spilianakis CG, Flavell RA. How are T_H1 and T_H2 effector cells made. Curr Opin Immunol, 2009, 21(2): 153-160.

[11] Dong C, Flavell RA. Control of T helper cell differentiation—in search of master genes. Sci STKE, 2000, 2000(49): pe1.

[12] Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol, 2003, 3(2): 133-146.

[13] Powrie F, Leach MW, Mauze S. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RB^hi CD4⁺ T cells. Immunity, 1994, 1(7): 553-562.

[14] Tu E, Ang DK, Bellingham SA. Both IFN-γ and IL-17 are required for the development of severe autoimmune gastritis. Eur J Immunol, 2012, 42(10): 2574-2583.

[15] Ouyang W, Ranganath SH, Weindel K. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity, 1998, 9(5): 745-755.

[16] Anderson MK. Changing course by lymphocyte lineage redirection. Nat Immunol, 2013, 14(3): 199-201.

[17] Brandtzaeg P, Pabst R. Let’s go mucosal: communication on slippery ground. Trends Immunol, 2004, 25(11): 570-577.

[18] Taylor MD, van der Werf N, Maizels RM. T cells in helminth infection: the regulators and the regulated. Trends Immunol, 2012, 33(4): 181-189.

[19] Lloyd CM, Hessel EM. Functions of T cells in asthma: more than just T_H2 cells. Nat Rev Immunol, 2010, 10(12): 838-848.

[20] Dong C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol, 2006, 6(4): 329-333.

[21] Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol, 2008, 8(5): 337-348.

[22] Schambach F, Schupp M, Lazar MA. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol, 2007, 37(9): 2396-2399.

[23] Bettelli E, Oukka M, Kuchroo VK. T_H-17 cells in the circle of immunity and autoimmunity. Nat Immunol, 2007, 8(4): 345-350.

[24] Ghoreschi K, Laurence A, Yang XP. Generation of pathogenic T_H17 cells in the absence of TGF-β signalling. Nature, 2010, 467(7318): 967-971.

[25] Maruyama T, Li J, Vaque JP. Control of the differentiation of regulatory T cells and T_H17 cells by the DNA-binding inhibitor Id3. Nat Immunol, 2011, 12(1): 86-95.

[26] Locksley RM. Nine lives: plasticity among T helper cell subsets. J Exp Med, 2009, 206(8): 1643-1646.

[27] Veldhoen M, Uyttenhove C, van Snick J. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol, 2008, 9(12): 1341-1346.

[28] Schmitt E, Germann T, Goedert S. IL-9 production of naive CD4⁺ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol, 1994, 153(9): 3989-3996.

[29] Chang HC, Sehra S, Goswami R. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol, 2010, 11(6): 527-534.

[30] Temann UA, Geba GP, Rankin JA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med, 1998, 188(7): 1307-1320.

[31] Duhen T, Geiger R, Jarrossay D. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol, 2009, 10(8): 857-863.

[32] Trifari S, Kaplan CD, Tran EH. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T_H-17, T_H1 and T_H2 cells. Nat Immunol, 2009, 10(8): 864-871.

[33] Bird PI, Trapani JA, Villadangos JA. Endolysosomal proteases and their inhibitors in immunity. Nat Rev Immunol, 2009, 9(12): 871-882.

[34] Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol, 2011, 12(5): 383-390.

[35] Basu R, O’Quinn DB, Silberger DJ. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity, 2012, 37(6): 1061-1075.

[36] Boniface K, Bernard FX, Garcia M. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol, 2005, 174(6): 3695-3702.

[37] Zenewicz LA, Yancopoulos GD, Valenzuela DM. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity, 2008, 29(6): 947-957.

[38] Ouyang W, Valdez P. IL-22 in mucosal immunity. Mucosal Immunol, 2008, 1(5): 335-338.

[39] Ouyang W. Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine Growth Factor Rev, 2010, 21(6): 435-441.

[40] Chen W. Tregs in immunotherapy: opportunities and challenges. Immunotherapy, 2011, 3(8): 911-914.

[41] Chen W, Jin W, Hardegen N. Conversion of peripheral CD4⁺CD25⁻ naive T cells to CD4⁺CD25⁺ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med, 2003, 198(12): 1875-1886.

[42] Chen W, Konkel JE. TGF-beta and ‘adaptive’ Foxp3⁺ regulatory T cells. J Mol Cell Biol, 2010, 2(1): 30-36.

[43] Liu Y, Zhang P, Li J. A critical function for TGF-beta signaling in the development of natural CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Nat Immunol, 2008, 9(6): 632-640.

[44] Maruyama T, Konkel JE, Zamarron BF. The molecular mechanisms of Foxp3 gene regulation. Semin Immunol, 2011, 23(6): 418-423.

[45] Perruche S, Zhang P, Liu Y. CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med, 2008, 14(5): 528-535.

[46] Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity, 2009, 30(5): 616-625.

[47] Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell, 2000, 101(5): 455-458.

[48] Chen W, Jin W, Wahl SM. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4⁺ T cells. J Exp Med, 1998, 188(10): 1849-1857.

[49] Wahl SM, Vázquez N, Chen W. Regulatory T cells and transcription factors: gatekeepers in allergic inflammation. Curr Opin Immunol, 2004, 16(6): 768-774.

[50] Carpenter AC, Bosselut R. Decision checkpoints in the thymus. Nat Immunol, 2010, 11(8): 666-673.

[51] Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol, 2011, 11(7): 445-456.

[52] Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol, 2002, 2(5): 336-345.

[53] Ciofani M, Zúñiga-Pflücker JC. Determining γδ versus αβ T cell development. Nat Rev Immunol, 2010, 10(9): 657-663.

[54] Vantourout P, Hayday A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol, 2013, 13(2): 88-100.

[55] Bonneville M, O’Brien RL, Born WK. γδ T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol, 2010, 10(7): 467-478.

[56] Jameson J, Ugarte K, Chen N. A role for skin γδ T cells in wound repair. Science, 2002, 296(5568): 747-749.

[57] Simpson SJ, Holländer GA, Mizoguchi E. Expression of pro-inflammatory cytokines by TCR αβ⁺ and TCR γδ⁺ T cells in an experimental model of colitis. Eur J Immunol, 1997, 27(1): 17-25.

[58] Kanazawa H, Ishiguro Y, Munakata A. Multiple accumulation of Vδ2⁺ γδ T-cell clonotypes in intestinal mucosa from patients with Crohn’s disease. Dig Dis Sci, 2001, 46(2): 410-416.

[59] Shires J, Theodoridis E, Hayday AC. Biological insights into TCRγδ⁺ and TCRαβ⁺ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity, 2001, 15(3): 419-434.

[60] Cawthon AG, Lu H, Alexander-Miller MA. Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8αβ versus CD8αα expression. J Immunol, 2001, 167(5): 2577-2584.

[61] Gangadharan D, Lambolez F, Attinger A. Identification of pre- and postselection TCRαβ⁺ intraepithelial lymphocyte precursors in the thymus. Immunity, 2006, 25(4): 631-641.

[62] Konkel JE, Maruyama T, Carpenter AC. Control of the development of CD8αα⁺ intestinal intraepithelial lymphocytes by TGF-β. Nat Immunol, 2011, 12(4): 312-319.

[63] Denning TL, Granger SW, Granger S. Mouse TCRαβ⁺CD8αα intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses. J Immunol, 2007, 178(7): 4230-4239.

[64] Walker DM. Oral mucosal immunology: an overview. Ann Acad Med Singap, 2004, 33(4 Suppl): 27-30.

[65] Novak N, Haberstok J, Bieber T. The immune privilege of the oral mucosa. Trends Mol Med, 2008, 14(5): 191-198.

[66] Lü FX, Jacobson RS. Oral mucosal immunity and HIV/SIV infection. J Dent Res, 2007, 86(3): 216-226.

[67] Kiyono H, Fukuyama S. NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat Rev Immunol, 2004, 4(9): 699-710.

[68] Zuercher AW, Coffin SE, Thurnheer MC. Nasal-associated lymphoid tissue is a mucosal inductive site for virus-specific humoral and cellular immune responses. J Immunol, 2002, 168(4): 1796-1803.

[69] Barrett AW, Cruchley AT, Williams DM. Oral mucosal Langerhans’ cells. Crit Rev Oral Biol Med, 1996, 7(1): 36-58.

[70] Cutler CW, Jotwani R. Dendritic cells at the oral mucosal interface. J Dent Res, 2006, 85(8): 678-689.

[71] Dale BA, Fredericks LP. Antimicrobial peptides in the oral environment: expression and function in health and disease. Curr Issues Mol Biol, 2005, 7(2): 119-133.

[72] Gomes Pde S, Fernandes MH. Defensins in the oral cavity: distribution and biological role. J Oral Pathol Med, 2010, 39(1): 1-9.

[73] Hovav AH. Dendritic cells of the oral mucosa. Mucosal Immunol, 2014, 7(1): 27-37.

[74] Patinen P, Savilahti E, Hietanen J. Intraepithelial lymphocytes bearing the γ/δ receptor in the oral and jejunal mucosa in patients with dermatitis herpetiformis. Eur J Oral Sci, 1997, 105(2): 130-135.

[75] Walton LJ, Macey MG, Thornhill MH. Intra-epithelial subpopulations of T lymphocytes and Langerhans cells in oral lichen planus. J Oral Pathol Med, 1998, 27(3): 116-123.

[76] Cohen MS, Shaw GM, McMichael AJ. Acute HIV-1 Infection. N Engl J Med, 2011, 364(20): 1943-1954.

[77] Romani L. Immunity to fungal infections. Nat Rev Immunol, 2011, 11(4): 275-288.

[78] Huang W, Na L, Fidel PL. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis, 2004, 190(3): 624-631.

[79] Conti HR, Baker O, Freeman AF. New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome. Mucosal Immunol, 2011, 4(4): 448-455.

[80] Conti HR, Shen F, Nayyar N. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med, 2009, 206(2): 299-311.

[81] Cheng SC, van de Veerdonk F, Smeekens S. Candida albicans dampens host defense by downregulating IL-17 production. J Immunol, 2010, 185(4): 2450-2457.

[82] Cochran DL. Inflammation and bone loss in periodontal disease. J Periodontol, 2008, 79(8 Suppl): 1569-1576.

[83] Gemmell E, Yamazaki K, Seymour GJ. Destructive periodontitis lesions are determined by the nature of the lymphocytic response. Crit Rev Oral Biol Med, 2002, 13(1): 17-34.

[84] Wu RQ, Zhao XF, Wang ZY. Novel molecular events in oral carcinogenesis via integrative approaches. J Dent Res, 2011, 90(5): 561-572.

[85] Scully C, Carrozzo M. Oral mucosal disease: lichen planus. Br J Oral Maxillofac Surg, 2008, 46(1): 15-21.

[86] Dan H, Liu W, Zhou Y. Association of interleukin-8 gene polymorphisms and haplotypes with oral lichen planus in a Chinese population. Inflammation, 2010, 33(2): 76-81.

[87] Rhodus NL, Cheng B, Ondrey F. Th1/Th2 cytokine ratio in tissue transudates from patients with oral lichen planus. Mediators Inflamm, 2007, 2007: 19854.

[88] Bai J, Lin M, Zeng X. Association of polymorphisms in the human IFN-γ and IL-4 gene with oral lichen planus: a study in an ethnic Chinese cohort. J Interferon Cytokine Res, 2008, 28(6): 351-358.

[89] Zhang Y, Lin M, Zhang S. NF-κB-dependent cytokines in saliva and serum from patients with oral lichen planus: a study in an ethnic Chinese population. Cytokine, 2008, 41(2): 144-149.

[90] Zhang Y, Liu W, Zhang S. Salivary and serum interleukin-18 in patients with oral lichen planus: a study in an ethnic Chinese population. Inflammation, 2012, 35(2): 399-404.

[91] Taghavi Zenouz A, Pouralibaba F, Babaloo Z. Evaluation of serum TNF-α and TGF-β in patients with oral lichen planus. J Dent Res Dent Clin Dent Prospects, 2012, 6(4): 143-147.

[92] Bai J, Jiang L, Lin M. Association of polymorphisms in the tumor necrosis factor-α and interleukin-10 genes with oral lichen planus: a study in a Chinese cohort with Han ethnicity. J Interferon Cytokine Res, 2009, 29(7): 381-388.

[93] Novak N, Gros E, Bieber T. Human skin and oral mucosal dendritic cells as ‘good guys’ and ‘bad guys’ in allergic immune responses. Clin Exp Immunol, 2010, 161(1): 28-33.

[94] Mascarell L, Saint-Lu N, Moussu H. Oral macrophage-like cells play a key role in tolerance induction following sublingual immunotherapy of asthmatic mice. Mucosal Immunol, 2011, 4(6): 638-647.

[95] Chen W. IDO: more than an enzyme. Nat Immunol, 2011, 12(9): 809-811.

[96] Bohle B, Kinaciyan T, Gerstmayr M. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol, 2007, 120(3): 707-713.

[97] Yoshitomi T, Nakagami Y, Hirahara K. Intraoral administration of a T-cell epitope peptide induces immunological tolerance in Cry j 2-sensitized mice. J Pept Sci, 2007, 13(8): 499-503.

[98] Chen Q, Xia J, Lin M. Serum interleukin-6 in patients with burning mouth syndrome and relationship with depression and perceived pain. Mediators Inflamm, 2007, 2007: 45327.