Claudia J. Calder

A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN-γ Stimulation in Experimental Autoimmune Uveoretinitis

IFN-γ stimulates macrophage activation and NO production, which leads to destruction of the retina in experimental autoimmune uveoretinitis. In this study, we investigate the mechanism of disease resistance in TNF p55 receptor-deficient animals. We show that although T cell priming is relatively unaffected, macrophages lacking the TNF p55 receptor fail to produce NO following IFN-γ stimulation because of a requirement for autocrine TNF-α signaling through the TNF p55 receptor. In contrast to the impaired activation of NO synthesis, MHC class II up-regulation was indistinguishable in wild-type and TNFRp55−/− mice stimulated with IFN-γ. These defects could be overcome by stimulating macrophages with LPS. Together, these results show that selected aspects of IFN-γ activation are controlled by autocrine secretion of TNF-α, but that this control is lost in the presence of signals generated by pathogen-associated molecular patterns recognizing receptors.

Enhanced Tolerance to Autoimmune Uveitis in CD200-Deficient Mice Correlates with a Pronounced Th2 Switch in Response to Antigen Challenge

A single exposure to inhaled Ag 10 days before immunization leads to long term, Ag-specific tolerance. Respiratory tract myeloid APCs are implicated, but how regulation is invoked, and how tolerance is sustained are unclear. This study examines the in vivo function of the myeloid regulatory molecule CD200 in the process of tolerance induction. Despite earlier onset of experimental autoimmune uveitis in sham-tolerized, CD200-deficient mice, disease incidence and subsequent severity were actually reduced compared with those in wild-type mice. Protection was more effective and long term, lasting at least 28 days. Halting disease progression and tolerance in CD200−/− mice correlated with a marked increase in Th2-associated cytokine production by Ag-challenged splenocytes. Reduced overall disease and enhanced tolerance in the CD200-deficient mice in this model system were unexpected and may be related to altered populations of MHC class IIlow APC in the respiratory tract compared with wild-type mice together with associated activation of STAT6 in draining lymph nodes of tolerized mice. These data indicate that in the absence of default inhibitory CD200 receptor signaling, alternative, powerful regulatory mechanisms are invoked. This may represent either permissive dominant Th2 activation or an altered hierarchy of negative signaling by other myeloid cell-expressed regulatory molecules.

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

Macrophages (Mϕ) 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 Mϕin 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 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 that is necessary for the development but not the execution of this function.