Antigen-specific blockade of T cells in vivo using dimeric MHC peptide.
Ag-specific immune tolerance in clinical organ transplantation is currently an unrealized but critical goal of transplant biology. The specificity and avidity of multimerized MHC-peptide complexes suggests their potential ability to modulate T cell sensitization and effector functions. In this study, we examined the ability of MHC-peptide dimers to modulate T cell function both in vitro and in vivo. Soluble MHC dimers induced modulation of surface TCR expression and inhibited T cell cytolytic activity at nanomolar concentrations in vitro. Furthermore, engagement of TCR by soluble dimers resulted in phosphorylation of the TCR zeta-chain and recruitment and phosphorylation of zeta-associated protein-70 to the signaling complex, the latter of which increased upon dimer cross-linking. Significantly, Ag-specific inhibition of an alloreactive TCR-transgenic T cell population in vivo resulted in consequent outgrowth of an allogeneic tumor. The prolonged Ag-specific suppression of expansion and/or effector function of cognate T cells in vivo suggests that soluble MHC dimers may be a means of inducing sustained Ag-specific T cell unresponsiveness in vivo.
O'Herrin
S M
SM
The Ben May Institute for Cancer Research, Department of Pathology, University of Chicago, Chicago, IL 60637, USA. oherrin@surgery.wisc.edu
Slansky
J E
JE
Tang
Q
Q
Markiewicz
M A
MA
Gajewski
T F
TF
Pardoll
D M
DM
Schneck
J P
JP
Bluestone
J A
JA
D000818:Animals; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D006183:H-2 Antigens / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014181:Transplantation Immunology; D051746:ZAP-70 Protein-Tyrosine Kinase
D004268:DNA-Binding Proteins; D006183:H-2 Antigens; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse