There are numerous similarities between T-cell receptor (TCR)-mediated and cytokine-receptor-mediated signalling — both involve receptor-subunit clustering and the activation of tyrosine kinases. Cytokine signalling is regulated by the suppressor of cytokine signalling (SOCS) family, but whether SOCS proteins are also involved in TCR signalling remains unclear. Recent work from Banerjee and colleagues published in The Journal of Immunology implicates SOCS3 in the negative regulation of TCR signalling.

Initial experiments showed that the level of Socs3 mRNA in mouse primary CD4+ T cells increases after TCR ligation. The authors then used T-cell lines and primary T cells to investigate the effects of Socs3 on TCR signalling. The overexpression of Socs3 inhibited the activity of the interleukin-2 (IL-2) promoter in these cells after TCR ligation.

Further co-transfection experiments in Jurkat cells indicated that SOCS3 might suppress the transcriptional activation of the IL-2 promoter that is mediated by nuclear factor of activated T cells (NFAT). Normally, TCR engagement results in the rapid calcineurin-dependent translocation of NFAT transcription factors from the cytoplasm to the nucleus. The active maintenance of dephosphorylated NFAT in the nucleus is crucial to control the expression of genes such as that encoding IL-2, which is required for the proliferation and activation of effector T cells.

The overexpression of SOCS3 in Jurkat cells resulted in the inhibition of NFAT activity and reduced production of IL-2. NFAT dephosphorylation was less efficient in these cells, which implies that SOCS3 limits the activity of NFATp by inhibiting its dephosphorylation. Finally, Banerjee et al. showed that there is an interaction between SOCS3 and the catalytic subunit of calcineurin, the phosphatase that is responsible for the dephosphorylation of NFAT.

The authors are aware that these results are based on the overexpression of SOCS3 in T cells and, therefore, that further experiments are necessary to prove that SOCS3 regulates the activation of NFATp in vivo. The embryonic lethality of Socs3−/− mice precludes these studies at present, but the generation of chimeric mice in which only T cells are deficient for Socs3 will help to clarify this issue.