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.
Howard Hughes Medical Institute, Department of Immunology, University of Washington, Seattle 98195.
S C
SC
Jameson
F R
FR
Carbone
M J
MJ
Bevan
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