New regulator of calcium signalling

A protein known as SLAT (SWAP70-like adaptor of T cells) was recently identified, but elucidation of its function awaited further study. Now, reporting in The Journal of Clinical Investigation, Bécart et al. show that SLAT is required for T-cell development, activation and effector function, and it does this by controlling calcium signalling.

SLAT (also known as IBP) is a guanine-nucleotide-exchange factor that is known to be activated following ligation of the T-cell receptor (TCR). To investigate the physiological role of SLAT in T cells, Bécart et al. studied T-cell development in SLAT-deficient mice. Their analysis revealed that there was a defect at an early stage of thymocyte development in Slat^−/− mice, such that proliferation of thymocytes at the double negative 1 (DN1) stage was impaired. As a result, fewer CD4⁺ T cells and, to a lesser extent, CD8⁺ T cells were present in the periphery of Slat^−/− mice compared with wild-type mice.

Moreover, those CD4⁺ T cells that did populate the periphery in Slat^−/− mice showed markedly reduced proliferation and interleukin-2 production in response to TCR and CD28 ligation, although they proliferated normally in response to PMA (phorbol 12-myristate 13-acetate) plus ionomycin (stimuli known to bypass the TCR).

Previous studies had suggested that SLAT might be involved in T helper 2 (T_H2)-cell differentiation, so the authors next tested the ability of Slat^−/− mice to mount T_H2-cell-mediated lung inflammation. As expected, there was a marked reduction in T_H2-cell-mediated lung inflammation in Slat^−/− mice; unexpectedly, however, Slat^−/− mice also failed to mount T_H1-cell-mediated lung inflammatory responses, indicating that SLAT is involved in responses by both T_H1- and T_H2-cell subsets.

Further investigation into the activation defect in T cells from Slat^−/− mice indicated that the most marked defect was in the nuclear translocation of NFAT (nuclear factor of activated T cells) following TCR and CD28 stimulation. Consistent with this, the initial rise in the free intracellular Ca²⁺ concentration that should occur following TCR ligation to promote NFAT translocation was severely reduced in the absence of SLAT. This, the authors show, most likely reflects a defect in the release of Ca²⁺ from endoplasmic reticulum stores.

So, by controlling TCR-induced Ca²⁺ and NFAT signalling, SLAT is required for proper T-cell development and effector function.