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 Mϕ, as TNFR1−/− Mϕ are unable to suppress T-cell proliferation. This deficit in antigen-presenting cells results in a lack of production of prostaglandin E2 (PGE2) and nitric oxide, which are critical effector mechanisms that inhibit T-cell division. However, TNFR1 signalling is not required for the inhibitory function of Mϕ because we could circumvent the requirement for this receptor, by maturing Mϕ in the

presence of exogenous interferon-γ and PGE2. This produced TNFR1−/− Mϕ that inhibited T-cell proliferation and indicates that TNFR1 delivers a signal selleck products that is necessary for the development Selleck MG-132 but not the execution

of this function. Organ-specific autoimmune diseases, such as multiple sclerosis and inflammatory eye disease, are co-ordinated by the activation of autoantigen-specific T cells, which are recruited specifically to sites of disease.1,2. The release of inflammatory mediators leads to a leucocyte influx that consists of a complex mixture of cell types.3,4 For example, at the peak of experimental autoimmune uveoretinitis (EAU), the murine model of human inflammatory eye disease, we observe a heterogeneous population of cells including CD11b+ cells, which form the largest fraction of the immune cells present, with significant numbers of CD4+ T cells and smaller numbers of CD8+ T cells also detected.5–7 In this environment, the large majority of CD11b+ cells are usually described as macrophages (Mϕ); they release inflammatory mediators and act as professional antigen-presenting cells (APCs).8–10 They can stimulate autoantigen-specific CD4+ T cells, by presenting MHC class II-restricted

peptides and we have recently reported that Mϕ derived from the inflamed retina of mice with EAU can act as myeloid regulatory cells, inhibiting T-cell proliferation while allowing normal antigen-specific T-cell cytokine production.10 One important cytokine produced by Bcl-w activated Mϕ is tumour necrosis factor-α (TNF-α) and the expression of one of its receptors, TNFR1, is necessary for the normal development of organ-specific autoimmunity.11,12 Blocking signals through this receptor produces a number of important changes in Mϕ function, including the abrogation of nitric oxide (NO) release following interferon-γ (IFN-γ) stimulation,11 with a concomitant reduction in tissue damage. In murine EAU, the loss of TNFR1 signalling is also associated with a dramatic reduction in CD11b+ cell trafficking to the target organ, but an increase in the relative proportion of CD4+ cells within the target organ,10 suggesting that the control of T-cell proliferation by myeloid CD11b+ cells in EAU may be dependent on TNFR1 signalling.