Signalling

The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Ananieva, O. et al. Nature Immunol. 10 August 2008 (doi: 10.1038/ni.1644)

In addition to their role in pro-inflammatory signalling pathways, p38, extracellular-signal-regulated kinase 1 (ERK1) and ERK2 also function to control excessive inflammation. This study shows that mitogen- and stress-activated kinase 1 (MSK1) and MSK2, which are downstream of p38, ERK1 and ERK2, mediate negative feedback pathways that control Toll-like receptor (TLR)-induced inflammation. MSK1 and MSK2 are activated by TLR ligands in bone-marrow-derived macrophages, and loss of MSK1 and MSK2 expression in these cells resulted in higher pro-inflammatory cytokine production in response to lipopolysaccharide (LPS). Further analyses showed that MSKs induce the expression of the phosphatase DUSP1 (which inactivates p38) and the anti-inflammatory cytokine interleukin-10, through the activation of the transcription factors ATF1 and CREB. Mice deficient for both MSKs were hypersensitive to LPS-induced endotoxic shock, confirming their role as negative regulators of TLR-induced pro-inflammatory signals.

Natural killer T cells

Rapid NKT cell responses are self-terminating during the course of microbial infection. Chiba, A. et al. J. Immunol. 181, 2292–2302 (2008)

Natural killer T (NKT) cells have been implicated in various immune responses, but when they are activated and when their responses are terminated during the natural course of infection was not known. Chiba et al. infected mice with Mycobacterium bovis bacillus Calmette–Guérin and showed that NKT cells expand, proliferate and produce interferon-γ (IFNγ) early after infection. However, by day 14, NKT-cell numbers were markedly reduced owing to the induction of apoptosis, although MHC-restricted T cells were still expanding and actively producing IFNγ. The remaining NKT cells were unresponsive to T-cell receptor stimuli, even though the bacterial burden persisted. So, the authors propose that NKT cells participate during the early phase of the immune response, but the NKT-cell response is then terminated (by apoptotic contraction and unresponsiveness) once the adaptive immune response has been established.

Immune tolerance

Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Kazama, H. et al. Immunity 29, 21–32 (2008)

Necrotic cells are known to induce an immune response, whereas apoptotic cells are generally thought to promote immune tolerance in vivo through effects on dendritic cells. Now, a recent study has uncovered a mechanism that explains this differential immune response. The authors show that, in addition to the known requirement for caspase activation, the induction of tolerance to an antigen by apoptotic cells in vivo depends on high-mobility group box 1 protein (HMGB1) and the caspase-dependent generation of reactive oxygen species. Whereas HMGB1 release from necrotic cells can act as a danger signal for surrounding immune cells, this study shows that apoptotic cells release an oxidized form of HMGB1 that prevents an immune response in vivo and instead promotes tolerance to the antigen.