Innate Restraint

Science's STKE  18 Feb 2003:
Vol. 2003, Issue 170, pp. tw74-TW74
DOI: 10.1126/stke.2003.170.tw74

Pathogen-specific immunity is shaped by the activation of innate immune receptors during the early stages of infection, most prominently the Toll-like receptors (TLRs). These receptors have evolved to scrutinize the molecular signatures of different classes of pathogen. They help tailor the most appropriate adaptive immune response, or, in pathological cases, allow autoimmune and allergic responses to develop (see the Perspective by Powrie and Maloy). Pasare and Medzhitov show that the TLR sphere of influence extends to regulatory T (TR) cells, which are critical players in the management of T cell immunity. Accompanying the expected immune-response program initiated by activating TLR on dendritic cells, the potent suppressive effects of TR cells were also blocked. This effect depended directly on production of the cytokine interleukin-6, which desensitized target T lymphocytes to the inhibitory effects of TR cells. By lifting the suppression of TR cells only in cases where the innate immune system has been activated, the immune system has come up with an elegant solution to the problem of maintaining control without compromising on efficiency. Naturally occurring mutations in the FOXP3 gene in humans and mice have highlighted the role of this transcription factor in immune regulation. Hori et al. provide direct evidence that this gene mediates principal control over TR development. FOXP3 was expressed preferentially in TR cells, and transduction of FOXP3-negative T cells with a retroviral FOXP3-expressing vector caused these cells to suppress the proliferation of other T cells. The FOXP3-transduced cells also inhibited an aggressive form of T cell-driven inflammatory bowel disease in mice.

F. Powrie, K. J. Maloy, Regulating the regulators. Science 299, 1030-1031 (2003). [Summary] [Full Text]

C. Pasare, R. Medzhitov, Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033-1036 (2003). [Abstract] [Full Text]

S. Hori, T. Nomura, S. Sakaguchi, Control of regulatory T cell development by the transcription factor FOXP3. Science 299, 1057-1061 (2003). [Abstract] [Full Text]