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 exquisit e specificity, T cell clones selected for a given peptide can recogniz e other sequentially or structurally related peptides, Here, we have e xamined the immunogenicity and tolerogenicity of various self-peptides derived from region 61-80 of different MHC class I proteins co-expres sed 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 imm unization, L(d) 61-80-tolerized mice responded to K-k 61-80 hut not to L(d) 61-80. Thus, tolerance induction to L(d) 61-80 resulted in the e limination/inactivation of L(d) 61-80-reactive T cells including the s ubpopulation that cross-reacted with K-k 61-80. However, T cells that recognized Kk 61-80 exclusively were preserved. Moreover, we showed th at 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 diffe rent cross-reactive seif-peptides within the same individual.