T cell tolerance is influenced by concomitant T cell recognition of cross-reactive self-peptides.
Although the current dogma of T cell recognition stresses its exquisite specificity, T cell clones selected for a given peptide can recognize other sequentially or structurally related peptides. Here, we have examined the immunogenicity and tolerogenicity of various self-peptides derived from region 61-80 of different MHC class I proteins co-expressed in the same mouse. Following immunization of B10.A mice (K(k), A(k), E(k), L(d), D(d)) with self-L(d) 61-80 peptide, vigorous MHC class II-restricted T cell proliferation was elicited after restimulation with either the immunogen or with self-K(k) 61-80 but not with self-D(d) 61-80. Furthermore, adult B10.A mice, tolerized with L(d) 61-80 prior to immunization with L(d) 61-80 did not respond to challenge with L(d) 61-80 and the cross-reactive K(k) 61-80. However, following K(k) 61-80 immunization, L(d) 61-80-tolerized mice responded to K(k) 61-80 but not to L(d) 61-80. Thus, tolerance induction to L(d) 61-80 resulted in the elimination/inactivation of L(d) 61-80-reactive T cells including the subpopulation that cross-reacted with K(k) 61-80. However, T cells that recognized K(k) 61-80 exclusively were preserved. Moreover, we showed that immunization with K(k) 61-80 resulted in tolerance breakdown to the cross-reactive, dominant self-peptide D(b) 61-80 in B10.A(4R) mice (K(k), A(k), L(d),D(b)). Together, these results show that the autoimmune T cell repertoire is influenced by the concomitant recognition of different cross-reactive self-peptides within the same individual.
Tam
R C
RC
Department of Surgery, University of California at San Francisco 94143, USA.
Fedoseyeva
E V
EV
Moskalenko
M
M
Garovoy
M R
MR
Benichou
G
G
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D003429:Cross Reactions; D003433:Crosses, Genetic; D005260:Female; D006183:H-2 Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007108:Immune Tolerance; D007114:Immunization; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D010455:Peptides