The mechanisms by which a T cell detects antigen using its T cell antigen receptor (TCR) are crucial to our understanding of immunity and the harnessing of T cells therapeutically. A hallmark of the T cell response is the ability of T cells to quantitatively respond to antigenic ligands derived from pathogens while remaining inert to similar ligands derived from host tissues. Recent studies have revealed exciting properties of the TCR and the behaviors of its signaling effectors that are used to detect and discriminate between antigens. Here we highlight these recent findings, focusing on the proximal TCR signaling molecules Zap70, Lck, and LAT, to provide mechanistic models and insights into the exquisite sensitivity and specificity of the TCR.

T cell receptor (TCR) interactions with self-peptide-major histocompatibility complex (pMHC) are crucial to T cell development, but their role in peripheral T cell responses remains unclear. Specific and nonspecific stimulation of Listeria-specific LLO56 and LLO118 TCR transgenic T cells elicited distinct interleukin 2 (IL-2) and phospho-ERK responses, the strength of which was set in the thymus and maintained in the periphery in proportion to TCR-self-pMHC avidity. Withdrawal of self-pMHC markedly compromised LLO56 expansion to Listeria in vivo. Despite their markedly different self-reactivities, LLO56 and LLO118 bound cognate-pMHC with identical affinities, challenging associations made between these parameters. Our findings highlight a crucial role for selecting ligands encountered during thymic education in determining the intrinsic functionality of CD4+ T cells.

T cell-antigen receptor (TCR) signaling requires the sequential activities of the kinases Lck and Zap70. Upon TCR stimulation, Lck phosphorylates the TCR, thus leading to the recruitment, phosphorylation, and activation of Zap70. Lck binds and stabilizes phosho-Zap70 by using its SH2 domain, and Zap70 phosphorylates the critical adaptors LAT and SLP76, which coordinate downstream signaling. It is unclear whether phosphorylation of these adaptors occurs through passive diffusion or active recruitment. We report the discovery of a conserved proline-rich motif in LAT that mediates efficient LAT phosphorylation. Lck associates with this motif via its SH3 domain, and with phospho-Zap70 via its SH2 domain, thereby acting as a molecular bridge that facilitates the colocalization of Zap70 and LAT. Elimination of this proline-rich motif compromises TCR signaling and T cell development. These results demonstrate the remarkable multifunctionality of Lck, wherein each of its domains has evolved to orchestrate a distinct step in TCR signaling.

Self/non-self discrimination is central to T cell-mediated immunity. The kinetic proofreading model can explain T cell antigen receptor (TCR) ligand discrimination; however, the rate-limiting steps have not been identified. Here, we show that tyrosine phosphorylation of the T cell adaptor protein LAT at position Y132 is a critical kinetic bottleneck for ligand discrimination. LAT phosphorylation at Y132, mediated by the kinase ZAP-70, leads to the recruitment and activation Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: