Repertoire requirements of CD4+ T cells that prevent spontaneous autoimmune encephalomyelitis.
Spontaneous experimental autoimmune encephalomyelitis arises in 100% of mice exclusively harboring myelin basic protein-specific T cells, and can be prevented by a single injection of CD4+ T cells obtained from normal donors. Given the powerful regulatory effect of the transferred T cells, we further investigated their properties, and, in particular, their repertoire requirements. Transfer of monoclonal OVA-specific CD4+ T cells did not confer protection from disease even when present at very high proportions (about 80% of total lymphocytes). Lack of protection was also evident after immunization of these animals with OVA, indicating that not just any postthymic CD4+ T cells has the potential to become regulatory. However, protection was conferred by cells bearing limited TCR diversity, including cells expressing a single Valpha4 TCR chain or cells lacking N nucleotides. We also investigated whether coexpression of the myelin basic protein-specific TCR with another TCR in a single cell would alter either pathogenesis or regulation. This was not the case, as myelin basic protein-specific/OVA-specific recombinase activating gene-1-/- double TCR transgenic mice still developed experimental autoimmune encephalomyelitis spontaneously even after immunization with OVA. Based on this evidence, we conclude that CD4+ T regulatory cells do not express canonical TCRs and that the altered signaling properties brought about by coexpression of two TCRs are not sufficient for the generation of regulatory T cells. Instead, our results indicate that regulatory T cells belong to a population displaying wide TCR diversity, but in which TCR specificity is central to their protective function.
Olivares-Villagómez
D
D
Division of Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine, Sackler Institute of Graduate Biomedical Sciences, New York University Medical Center, New York, NY 10016, USA.
Wensky
A K
AK
Wang
Y
Y
Lafaille
J J
JJ
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D019673:Genes, T-Cell Receptor alpha; D007114:Immunization; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D010047:Ovalbumin