TNF&agr; in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases
HighlightsTNF&agr; mediates cell responses and inflammation by binding to TNF receptors 1 and 2.In T cells, TNF&agr; can promote cell death or proliferation depending on context.TNF&agr; enhances T cell responses but sustained exposure renders them hypo‐responsive.TNF&agr; signalling molecule polymorphisms are autoimmune disease susceptibility factors.Tregs and Th17 cells are modulated by TNF&agr; and its blockade alters their numbers. ABSTRACT TNF&agr; is a principal pro‐inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNF&agr; inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNF&agr; causes its effects by binding to either or both of two membrane‐bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNF&agr; and depending on whether the cytokine is membrane‐bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNF&agr; and T cell signalling proteins can significantly impact the outcome of TNF&agr; receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNF&agr;. However, recent evidence indicates that the relationship between TNF&agr; and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNF&agr; on different T cell subsets. This review will summarise knowledge on how TNF&agr; modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNF&agr; inhibitors.