TNFR1 signalling is a critical checkpoint for developing macrophages that control of T-cell proliferation

P>Macrophages (M phi) are professional antigen-presenting cells, but when they accumulate at sites of inflammation, they can inhibit T-cell proliferation. In experimental autoimmune uveoretinitis, this limits the expansion of T cells within the target organ. To define requirements for the elaboration of this outcome, we have generated populations of M phi in vitro that could also regulate T-cell responses; stimulating CD4+ T-cell activation and cytokine production, but simultaneously suppressing T-cell proliferation. When T cells are removed from the influence of such cells, normal T-cell responses are restored. We show that tumour necrosis factor 1 (TNFR1) signalling is a critical checkpoint in the development of such M phi, as TNFR1-/- M phi are unable to suppress T-cell proliferation. This deficit in antigen-presenting cells results in a lack of production of prostaglandin E-2 (PGE(2)) and nitric oxide, which are critical effector mechanisms that inhibit T-cell division. However, TNFR1 signalling is not required for the inhibitory function of M phi because we could circumvent the requirement for this receptor, by maturing M phi in the presence of exogenous interferon-gamma and PGE(2). This produced TNFR1-/- M phi that inhibited T-cell proliferation and indicates that TNFR1 delivers a signal that is necessary for the development but not the execution of this function.