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 abi lity 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 surfac e TCR expression and inhibited T cell cytolytic activity at nanomolar conce ntrations in vitro. Furthermore, engagement of TCR by soluble dimers result ed in phosphorylation of the TCR C-chain and recruitment and phosphorylatio n of xi -associated protein-70 to the signaling complex, the latter of whic h increased upon dimer cross-linking. Significantly, Ag-specific inhibition of an alloreactive TCR-transgenic T cell population in vivo resulted in co nsequent outgrowth of an allogeneic tumor. The prolonged Ag-specific suppre ssion of expansion and/or effector function of cognate T cells in vivo sugg ests that soluble MHC dimers may be a means of inducing sustained Ag-specif ic T cell unresponsiveness in vivo.