Age-associated decreases in primary CD8 T cell responses occur, in part, due to direct effects on naive CD8 T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated "virtual memory" (T) cells, but their contribution to age-related functional decline is unclear. Here, we show that T cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (T cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged T cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population.
T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRβ-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db–NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.