Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells.
A previous report showed that the proliferative response of helper T cells to class II major histocompatibility complex (MHC)-restricted antigens can be inhibited by analogues of the antigen, which act as T cell receptor (TCR) antagonists. Here we define and analyze peptide variants that antagonize various functions of class I MHC-restricted cytotoxic T lymphocyte (CTL) clones. Of 64 variants at individual TCR contact sites of the Kb-restricted octamer peptide ovalbumin257-264 (OVAp), a very high proportion (40%) antagonized lysis by three OVAp-specific CTL clones. This effect was highly clone specific, since many antagonists for one T cell clone have differential effects on another. We show that this inhibition of CTL function is not a result of T cell-T cell interaction, precluding veto-like phenomena as a mechanism for antagonism. Moreover, we present evidence for direct interaction between the TCR and antagonist-MHC complexes. In further analysis of the T cell response, we found that serine esterase release and cytokine production are susceptible to TCR antagonism similarly to lysis. Ca2+ flux, an early event in signaling, is also inhibited by antagonists but may be more resistant to the antagonist effect than downstream responses.
Jameson
S C
SC
Howard Hughes Medical Institute, Department of Immunology, University of Washington, Seattle 98195.
Carbone
F R
FR
Bevan
M J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004950:Esterases / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin; D004950:Esterases; C022635:serine esterase; D002118:Calcium