T cell-dependent autoimmune diseases are characterized by the expansion of T cell clones that recognize immunodominant epitopes on the target antigen. As a consequence, for a given autoimmune disorder, pathogenic T cell clones express T cell receptors with a limited number of variable regions that define antigenic specificity. Qa-1, a MHC class I-like molecule, presents peptides from the variable region of TCRs to Qa-1-restricted CD8+ T cells. The induction of V？-specific CD8+ T cells has been harnessed in an immunotherapeutic strategy known as the “T cell vaccination” (TCV) that comprises the injection of activated and attenuated CD4+ T cell clones so as to induce protective CD8+ T cells. We hypothesized that Qa-1-restricted CD8+ regulatory T cells could also constitute a physiologic regulatory arm of lymphocyte responses upon expansion of endogenous CD4+ T cells, in the absence of deliberate exogenous T cell vaccination. We immunized mice with two types of antigenic challenges in order to sequentially expand antigen-specific endogenous CD4+ T cells with distinct antigenic specificities but characterized by a common V？ chain in their TCR. The first immunization was performed with a non-self antigen while the second challenge was performed with a myelin-derived peptide known to drive experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that regulatory V？-specific Qa-1-restricted CD8+ T cells induced during the first endogenous CD4+ T cell responses are able to control the expansion of subsequently mobilized pathogenic autoreactive CD4+ T cells. In conclusion, apart from the immunotherapeutic TCV, Qa-1-restricted specialized CD8+ regulatory T cells can also be induced during endogenous CD4+ T cell responses. At variance with other regulatory T cell subsets, the action of these Qa-1-restricted T cells seems to be restricted to the immediate re-activation of CD4+ T cells.
References
[1]
Ben-Nun A, Wekerle H, Cohen IR (1981) Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein. Nature 292: 60–61.
[2]
Jiang H, Kashleva H, Xu LX, Forman J, Flaherty L, et al. (1998) T cell vaccination induces T cell receptor Vbeta-specific Qa-1-restricted regulatory CD8(+) T cells. Proc Natl Acad Sci U S A 95: 4533–4537.
[3]
Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, et al. (2004) Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol 5: 516–523.
[4]
Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc 1: 1810–1819.
[5]
Lider O, Reshef T, Beraud E, Ben-Nun A, Cohen IR (1988) Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science 239: 181–183.
[6]
Itoh Y, Kajino K, Ogasawara K, Takahashi A, Namba K, et al. (1997) Interaction of pigeon cytochrome c-(43-58) peptide analogs with either T cell antigen receptor or I-Ab molecule. Proc Natl Acad Sci U S A 94: 12047–12052.
[7]
Kariyone A, Tamura T, Kano H, Iwakura Y, Takeda K, et al. (2003) Immunogenicity of Peptide-25 of Ag85B in Th1 development: role of IFN-gamma. Int Immunol 15: 1183–1194.
[8]
Koh DR, Fung-Leung WP, Ho A, Gray D, Acha-Orbea H, et al. (1992) Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice. Science 256: 1210–1213.
[9]
Jiang H, Braunstein NS, Yu B, Winchester R, Chess L (2001) CD8+ T cells control the TH phenotype of MBP-reactive CD4+ T cells in EAE mice. Proc Natl Acad Sci U S A 98: 6301–6306.
[10]
Li J, Goldstein I, Glickman-Nir E, Jiang H, Chess L (2001) Induction of TCR Vbeta-specific CD8+ CTLs by TCR Vbeta-derived peptides bound to HLA-E. J Immunol 167: 3800–3808.
[11]
Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, et al. (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10: 514–523.
[12]
Panoutsakopoulou V, Huster KM, McCarty N, Feinberg E, Wang R, et al. (2004) Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes. J Clin Invest 113: 1218–1224.
[13]
Bousso P (2008) T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol 8: 675–684.
[14]
Varthaman A, Khallou-Laschet J, Clement M, Fornasa G, Kim HJ, et al. Control of T cell reactivation by regulatory Qa-1-restricted CD8+ T cells. J Immunol 184: 6585–6591.
[15]
Kim HJ, Verbinnen B, Tang X, Lu L, Cantor HInhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467: 328–332.
[16]
DeCloux A, Woods AS, Cotter RJ, Soloski MJ, Forman J (1997) Dominance of a single peptide bound to the class I(B) molecule, Qa-1b. J Immunol 158: 2183–2191.
[17]
Chun T, Aldrich CJ, Baldeon ME, Kawczynski LV, Soloski MJ, et al. (1998) Constitutive and regulated expression of the class IB molecule Qa-1 in pancreatic beta cells. Immunology 94: 64–71.
[18]
Sullivan BA, Kraj P, Weber DA, Ignatowicz L, Jensen PE (2002) Positive selection of a Qa-1-restricted T cell receptor with specificity for insulin. Immunity 17: 95–105.
[19]
Michaelsson J, Teixeira de Matos C, Achour A, Lanier LL, Karre K, et al. (2002) A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. J Exp Med 196: 1403–1414.
[20]
O'Callaghan CA, Tormo J, Willcox BE, Braud VM, Jakobsen BK, et al. (1998) Structural features impose tight peptide binding specificity in the nonclassical MHC molecule HLA-E. Mol Cell 1: 531–541.
[21]
Tang X, Maricic I, Purohit N, Bakamjian B, Reed-Loisel LM, et al. (2006) Regulation of immunity by a novel population of Qa-1-restricted CD8alphaalpha+TCRalphabeta+ T cells. J Immunol 177: 7645–7655.
[22]
Smith TR, Tang X, Maricic I, Garcia Z, Fanchiang S, et al. (2009) Dendritic cells use endocytic pathway for cross-priming class Ib MHC-restricted CD8alphaalpha+TCRalphabeta+ T cells with regulatory properties. J Immunol 182: 6959–6968.
