Attenuated T cell responses to a high-potency ligand in vivo

Αβ t cell receptor (tcr) recognition of foreign peptides bound to major histocompatibility complex (pmhc) molecules on the surface of antigen presenting cells is a key event in the initiation of adaptive cellular immunity. in vitro,high-affinity binding and/or long-lived interactions between tcrs and pmhc correlate with high-potency t cell activation. however,less is known about the influence of tcr/pmhc interaction parameters on t cell responses in vivo. we studied the influence of tcr/pmhc binding characteristics on in vivo t cell immunity by tracking cd4+ t cell activation,effector,and memory responses to immunization with peptides exhibiting a range of tcr/pmhc half-lives and in vitro t cell activation potencies. contrary to predictions from in vitro studies,we found that optimal in vivo t cell responses occur to ligands with intermediate tcr/pmhc half-lives. the diminished in vivo responses we observed to the ligand exhibiting the longest tcr/pmhc half-life were associated with attenuation of intracellular signaling,expansion,and function over a broad range of time points. our results reveal a level of control over t cell activation in vivo not recapitulated in in vitro assays and highlight the importance of considering in vivo efficacy of tcr ligands as part of vaccine design. © 2010 corse et al.