Fig. 1.

αβTCR and preTCR structure and function. a. The αβTCR is a multimeric cell surface receptor composed of eight membrane-spanning subunits. The TCRα and β, which comprise the ligand-recognition portions of the receptor, are associated as a disulfide-linked heterodimer, with variable regions as well as constant and TM domains but lacking signaling elements. Invariant CD3εγ and εδ subunits without pMHC ligand-binding capacity contain extracellular Ig-like domains which mediate subunit pairing, TM domains, and intracellular domains responsible for signaling. CD3ζζ exists as a disulfide-bonded homodimer with TM and intracellular signaling domains, but possesses no extracellular domain. b. The preTCR incorporates pTα instead of TCRα prior to the DN to DP transition (see d. below) but the receptor complexes are otherwise identical with respect to CD3 components (not shown). The Cβ FG loop is represented in light blue within each receptor. The preTCR and αβTCR recognize pMHC ligand using overlapping but distinct surfaces. Note the Vβ patch region important for preTCR-pMHC interaction is occluded by the presence of the TCRα subunit in the TCR. The surface exposed CDR1–3 region of each ligand binding subunit is shown as denoted by CDRα and CDRβ labels. Additionally, the intracellular C-terminal tail of pTα that may possess signaling capacity is depicted. c. T cell function is governed by its mobility. The T cell attaches to an APC which presents target pMHC. As the T cell scans the APC (top panel), its surface receptors are exposed to a wide range of forces which engender force-dependent changes (bottom panels) within the TCR ectodomains, TMs, and intracellular ITAM signaling motifs as well as, potentially, proximal membrane lipid environment. For simplicity, CD4 and CD8 co-receptors and CD28 and CD80/86 costimulatory interactions are not shown. d. Developmental progression within the thymus. Thymocyte development is a process orchestrated by spatial migration to and within the thymus, somatic genetic rearrangements, pMHC ligand-mediated β-selection by the preTCR and positive and negative selection by the αβTCR. Abbreviations used for thymocyte subpopulations: Thymus specific progenitor, TSP; CD4 and CD8 Double Negative (DN) Stage 3 and 4, DN3 and DN4 with preceding stages DN1 and DN2 omitted for clarity; CD4 and CD8 Double positive, DP; CD4 or CD8 Single positive, CD4 SP or CD8 SP.