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 Mϕ 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 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 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 Mϕ because we could circumvent the requirement for this receptor, by maturing Mϕ in the presence of exogenous interferon-γ and PGE(2). 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.
Department of Cellular and Molecular Medicine, School of Medical Sciences, Bristol, UK.
Ben J E
BJ
Raveney
David A
DA
Copland
Claudia J
CJ
Calder
Andrew D
AD
Dick
Lindsay B
LB
Nicholson
D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D047888:Receptors, Tumor Necrosis Factor, Type I; D007371:Interferon-gamma; D015232:Dinoprostone