A Calming Touch

Science Signaling  14 Jul 2009:
Vol. 2, Issue 79, pp. ec233
DOI: 10.1126/scisignal.279ec233

Inflammasomes are cytosolic protein complexes that respond to various pathogen- or danger-associated signals by activating caspase-1, which processes the precursor form of the proinflammatory cytokine interleukin-1β (IL-1β) so that it can be secreted. Because of its potency, IL-1β can cause tissue damage and disease if unchecked. Noting that certain lymphocytes inhibit innate immune cell–dependent inflammation, Guarda et al. investigated the effects of lymphocytes on the inflammasome. Incubation of mouse bone marrow–derived macrophages treated with lipopolysaccharide (LPS, which drives expression of the gene encoding pro-IL-1β) and ATP [which activates an inflammasome containing NOD-like receptor protein 3 (NLRP3)] with activated memory CD4+ T cells decreased their secretion of IL-1β. Memory CD4+ T cells that had not been activated through stimulation of their T cell receptors could not inhibit IL-1β secretion by the macrophages, nor could other T cell subsets. In addition, memory CD4+ T cells did not inhibit the production of inflammasome-independent inflammatory cytokines and chemokines. Inhibition of inflammasome activity required contact between the activated T cells and the macrophages and depended on the presence of members of the membrane-bound, tumor necrosis factor family of ligands, such as CD40L, which is found on activated T cells and binds to CD40 on macrophages. In a mouse model of peritonitis that depends on NLRP3, activation of T cells with antigen in the context of macrophage stimulation resulted in less inflammation than occurred in mice whose T cells were not activated. Together, these data suggest that memory CD4+ T cells act to specifically inhibit the potentially damaging inflammasome-dependent responses of macrophages while leaving unscathed other inflammatory components required for an effective innate immune response.

G. Guarda, C. Dostert, F. Staehli, K. Cabalzar, R. Castillo, A. Tardivel, P. Schneider, J. Tschopp, T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 460, 269–273 (2009). [PubMed]