Editors' ChoiceImmunology

TRAF3 Restrains Production of Tregs

Sci. Signal.  19 Aug 2014:
Vol. 7, Issue 339, pp. ec220
DOI: 10.1126/scisignal.2005811

Regulatory T cells (Tregs) are immunosuppressive cells, which inhibit the effector T cells responsible for mediating immune responses. Control of the numbers of Tregs is critical; too few will lead to autoimmunity, and too many will lead to impaired immune responses. Noting that the adaptor protein TRAF3 [tumor necrosis factor (TNF) receptor–associated factor 3] has both receptor- and cell type–specific roles in immune cells, Yi et al. generated mice with a T cell–specific deficiency in TRAF3 (T-Traf3–/– mice). Compared with littermate control mice, T-Traf3–/– mice had two- to threefold increased numbers of Tregs; however, there were no differences in the ability of Tregs from either mouse strain to survive or undergo apoptosis, nor were there differences in the abundance of Treg-specific transcription factor Foxp3. Functionally, Tregs from T-Traf3–/– mice and control mice had similar immunosuppressive function in vitro and in vivo. The generation of Tregs depends on the cytokine interleukin-2 (IL-2). T-Traf3–/– mice and littermate controls had similar numbers of Treg precursor cells, and Treg precursors from both strains of mice had similar amounts of the three subunits of the IL-2 receptor (IL-2R). However, when similar numbers of Treg precursors were stimulated with IL-2 in culture, more T-Traf3–/– Tregs were produced than were Tregs from the littermate controls. Western blotting analysis revealed that the IL-2–dependent activation of the kinases JAK1 and JAK3 and of the transcription factor STAT5 was increased in T-Traf3–/– Treg precursors compared with that in control Treg precursors. Immunoprecipitation studies showed that TRAF3 was recruited to the IL-2R complex in response to IL-2 and that it also associated with the phosphatase TCPTP, which inhibits JAK1 and JAK3 signaling. Together, these data suggest that TRAF3 recruits TCPTP to the IL-2R complex in Treg precursors to limit Treg production. This pathway might be targeted therapeutically to manipulate Treg numbers.

Z. Yi, W. W. Lin, L. L. Stunz, G. A. Bishop, The adaptor TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating signaling via the receptor for IL-2. Nat. Immunol. 2014 July 20. doi: 10.1038/ni.2944 [Epub ahead of print] [PubMed]

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