title: Attenuated T cell responses to a high-potency ligand in vivo.
abstract: 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.
authors.affiliation: Department of Immunology, Howard Hughes Medical Institute and Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Corse
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gottschalk
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D008024:Ligands; D008213:Lymphocyte Activation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008024:Ligands; D016693:Receptors, Antigen, T-Cell, alpha-beta