Signaling in thymic selection

Abstract

T cell receptor signaling allows the developing thymocyte to undergo positive or negative selection, which is required for the formation of a useful mature T cell repertoire. Recent developments include the finding that much of the Lck kinase (required to initiate T cell signaling) is already in an active configuration before signaling. The analog strength of antigen binding to the T cell receptor binding may be translated into a digital signal by the amount of time the TCR is paired with a co-receptor carrying Lck. Downstream, the cellular localization of MAP kinase signaling is determined by the strength of the signal and in turn predicts positive or negative selection. A novel protein, Themis, is important in crossing the positive selection developmental checkpoint, but its mode of action is still uncertain. Commitment to the CD4 or CD8 lineage is influenced by the amount of ZAP-70 signaling and also by closely regulated responsiveness to intrathymic cytokines such as IL7.

Figure 1

Prior to antigen encounter, the CD8 co-receptor carries a pre-activated Lck molecule, placing the thymocyte in “stand-by” mode (A), ready to initiate a signal once cognate antigen co-engages CD8 and the TCR (B). If the pMHC co-engages TCR and CD8 for a sufficiently long time, a “zippered” structure is formed between the membrane proximal domains of CD8β and the TCR’s α chain, which brings the pre-activated Lck into the CD3 complex, leading to high level phosphorylation of the ζ chain ITAMs (C). Once enough ζ-phosphorylated TCRs are formed, they are able to bind ZAP-70. A second round of Lck phosphorylation is responsible for phosphorylating ZAP-70 at Y319, but the phosphorylation at Y493 is brought about by ZAP-70 trans-phosphorylation (D).