Altered differentiation, diminished pathogenicity, and regulatory activity of myelin-specific T cells expressing an enhanced affinity TCR.
Whereas increased affinity enhances T cell competitiveness after immunization, the role of affinity in modulating the pathogenicity of self-reactive T cells is less established. To assess this, we generated two myelin-specific, class II MHC-restricted TCR that differ only in a buried hydroxymethyl that forms a common TCR β-chain V region variant. The variation, predicted to increase TCR stability, resulted in a ~3log(10) difference in TCR sensitivity with preserved fine specificity. The high-affinity TCR markedly diminished T cell pathogenicity. T cells were not deleted, did not upregulate Foxp3, and barring disease induction were predominantly naive. However, high-affinity CD4(+) T cells showed an altered cytokine profile characterized by the production of protective cytokines prior to experimental allergic encephalomyelitis induction and decreased effector cytokines after. Further, the high-affinity TCR promoted the development of CD4(-)CD8(-) and CD8(+) T cells that possessed low intrinsic pathogenicity, were protective even in small numbers when transferred into wild-type mice and in mixed chimeras, and outcompete CD4(+) T cells during disease development. Therefore, TCR affinities exceeding an upper affinity threshold may impede the development of autoimmunity through altered development and functional maturation of T cells, including diminished intrinsic CD4(+) T cell pathogenicity and the development of CD4(-)Foxp3(-) regulatory populations.
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Rajshekhar
R
Alli
Phuong
P
Nguyen
Terrence L
TL
Geiger
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005434:Flow Cytometry; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology* / Q000276:immunology*
D001324:Autoantigens; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell