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T cells play a major role in producing adaptive immune responses to microbes and cancers. T-cell development occurs in the thymus, starting from hematopoietic stem cells. There, CD4–CD8– double-negative (DN) thymocytes that generate a functional T-cell receptor (TCR) β-chain express on their surface the pre-TCR (preTCR). Unlike the TCR itself, which comprises an α-chain and a β-chain, the preTCR consists of a TCR β-chain and an invariant preTCR α-chain (pTα) (1) (Fig. 1A). Both the TCR and preTCR are associated with CD3 molecules, which transduce activation signals to the cell. The reason the preTCR lacks a TCR α-chain is that TCRβ gene rearrangements precede those of TCRα genes. Expression of the preTCR enables DN cells with productive TCRβ rearrangements to differentiate into CD4+CD8+ double-positive (DP) thymocytes. This process, known as β-selection, is the first major checkpoint in T-cell development. Signaling through the preTCR terminates TCRβ rearrangements, rescues cells from apoptosis, enables DN thymocytes to differentiate to DP thymocytes, and triggers TCRα rearrangements. In PNAS, Mallis et al. (2) present another advance in the understanding of β-selection. PreTCR structure and interactions. (A) Crystal structure of the preTCR (PDB ID code 3OF6) (1). Regions of Vβ found to interact with pMHC in NMR titration experiments (CDR1, CDR3, and Vβ patch) (2) are depicted as molecular surfaces. (B) Cartoon representation of the preTCR structure in A showing the proposed interaction with a pMHC class I (pMHC I) self-ligand. The MHC class I heavy chain is drawn as three light blue ovals; β2-microglobulin (β2m) is an orange sphere; MHC-bound peptide is a red ball. The preTCR is perpendicular to the plane of the thymocyte membrane. Associated with the Cβ domain at the base of the preTCR is the CD3εγ heterodimer (9, 10). For clarity, other CD3 subunits …

Pre–T-cell receptor binds MHC: Implications for thymocyte signaling and selection