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Differential Activation of T Cells by Natural Antigen Peptide Analogues: Influence on Autoimmune and Alloimmune In Vivo T Cell Responses¹

University of California at San Francisco School of Medicine, Department of Surgery, Immunogenetics and Transplantation Laboratory at Davies Medical Center, San Francisco, CA 94114

Recent studies using synthetic altered peptide ligands (Analogues) have led to the fine dissection of TCR-mediated T cell functions elicited by Ag recognition. Certain Analogues behave as full agonists of the antigenic peptide while others are partial agonists in that they only trigger selected T cell functions. Additionally, peptide Analogues can behave as antagonists by inhibiting functions of T cell clones when coincubated with the wild-type peptide. In fetal thymic organ cultures, synthetic altered peptide ligands can impact T cell repertoire selection. However, the influence of naturally occurring peptide Analogues on T cell immunity in vivo remains hypothetical. We previously reported that, in B10.A mice, immunogenicity and tolerogenicity of the self-MHC class I peptide, L^d 61-80, were influenced by the presentation of a cross-reactive self-peptide, K^k 61-80. Here, we show that K^k 61-80 self-peptide represents a partial agonist of L^d 61-80 in that it induced the proliferation but not the lymphokine production of L^d 61-80-primed T cells. Next, we showed that presentation of K^k 61-80 Analogue peptide mediated T cell tolerance toward L^d 61-80 self-peptide. Alternatively, when L^d protein represented an alloantigen displayed on transplanted cells, immunization with K^k 61-80 Analogue sensitized recipient mice to L^d 61-80 peptide, thus inducing potent immune responses to donor cells. These results show that the presentation of natural Analogue peptides may represent an essential component of T cell responses involved in autoimmunity and transplant rejection.