THEMIS: a critical TCR signal regulator for ligand discrimination.

Genetic approaches identified THEMIS as a critical element driving positive selection of CD4(+)CD8(+) thymocytes towards maturation. THEMIS is expressed only in the T-cell lineage, and is recruited to the proximity of signaling T-cell antigen receptors (TCR) by association with the membrane scaffold LAT. However, its molecular role remained an enigma until recently. Conventionally positively-selected T-cells are lacking in THEMIS-deficient mice, leading to the initial hypothesis that THEMIS positively regulates TCR signaling. Recent data show that THEMIS deficiency increases rather than decreases TCR signaling, leading to augmented apoptosis. The finding that THEMIS is constitutively bound to the tyrosine phosphatases SHP1 or SHP2, provides a mechanism for THEMIS action. When recruited onto LAT, THEMIS-SHP promotes immediate dephosphorylation of TCR-proximal signaling components. This negative feedback is central in setting sharp signaling thresholds and helps explain the exquisite ligand discrimination by the TCR, particularly during thymocyte selection.