Progranulin promotes tumour necrosis factor‐induced proliferation of suppressive mouse CD 4 + F oxp3 + regulatory T cells

Summary Progranulin ( PGRN ) is a pleiotropic growth factor with immunosuppressive properties. Recently, it was reported that PGRN was an antagonist of tumour necrosis factor ( TNF ) receptors, preferentially for TNFR 2. However, we and others showed that TNF – TNFR 2 interaction was critical for the activation and expansion of functional CD 4 +   F oxp3 + regulatory T ( T reg) cells. We therefore examined the effect of PGRN on the proliferation of naturally occurring murine suppressive T reg cells induced by TNF . Consistent with our previous reports, TNF overcame the hyporesponsiveness of highly purified T reg cells to T ‐cell receptor stimulation. Furthermore, in the presence of interleukin‐2, TNF preferentially stimulated proliferation of T reg cells contained in unfractionated CD 4 cells. These effects of TNF on suppressive T reg cells were markedly increased by exogenous PGRN . TNF and TNFR 2 interactions are required for this effect of PGRN , because the PGRN by itself did not stimulate T reg cell proliferation. The effect of PGRN on T reg cells was abrogated by antibody against TNFR 2, and T reg cells deficient in TNFR 2 also failed to respond to PGRN . Furthermore, PGRN also enhanced the proliferative responses of effector T cells to TNF , but to a lesser extent than that of T reg cells, presumably caused by the different levels of TNFR 2 expression on these two subsets of CD 4 cells. Hence, our data clearly show that PGRN promotes, rather than inhibits, the functional consequence of TNF – TNFR 2 interaction on T reg cells.