INDUCTION OF A HETEROGENEOUS TCR REPERTOIRE IN (PL JXSJL/J)F1 MICE BYMYELIN BASIC-PROTEIN PEPTIDE AC1-11 AND ITS ANALOG AC1-11[4A]/

Experimental autoimmune encephalomyelitis (EAE) serves as a rodent mod el of the autoimmune disease multiple sclerosis. In mice, EAE is induc ed by immunizing with spinal cord homogenate, components of the myelin sheath, such as myelin basic protein (MBP) or proteolipid protein (PL P), or peptides derived from these components. EAE can be induced in H -2(u) or (H-2(u) x H-2(5))F1 mice with the N-terminal peptide of MBP, Acl-11. Coimmunization with Ad-II and Acl-11[4A], an analog in which l ysine at position four is substituted with alanine, prevents EAE. The mechanism of inhibition has not been elucidated, but probably does not work through MHC blockade, T cell anergy or clonal elimination of enc ephalitogenic T cells. We have isolated T cell clones and hybridomas f rom (PL/J x SJL/J)FI mice immunized with either Acl-11 alone or Acl-11 and Acl-11[4A] and analysed these cells for differences in their T ce ll receptor repertoire and in vitro response. Although T cells elicite d by coinjection of Acl-11 and Acl-11[4A] expressed TCR that used V al pha and V beta gene elements similar to those elicited by Acl-11 alone , they differed in the sequences of the junctional region of the alpha chain. Most of these T cells also responded less well to Acl-ll in vi tro, suggesting that coinjection of Acl-11 and Acl-11[4A] preferential ly activates T cells bearing TCR of different affinity for Acl-11 boun d to I-A(u), and which may therefore be less encephalitogenic. Further more, our results show that a more diverse repertoire of V alpha and V beta genes are elicited by Acl-11 in (PL/J x SJL/J)F1 mice compared t o PL/J and B10.PL mice, providing further evidence that a restricted T CR repertoire is not required for the development of autoimmune diseas e. (C) 1998 Elsevier Science Ltd. All rights reserved.