Immune regulation

TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Sun, H. et al. Cell 133, 415–426 (2008)

A newly discovered member of the tumour-necrosis-factor-α-induced protein 8 (TNFAIP8) family known as TIPE2 has been identified as a crucial regulator of immune responses. This protein was found to negatively regulate T-cell activation, as well as Toll-like receptor signalling in innate immune cells and B cells. Accordingly, TIPE2-deficient mice spontaneously developed fatal autoimmunity and were more susceptible to endotoxin-induced septic shock than wild-type mice. Closer examination of the molecular function of TIPE2 revealed its ability to inhibit the pro-inflammatory activator protein 1 (AP1) and nuclear factor-κB (NF-κB) pathways. Furthermore, TIPE2 promoted activation-induced cell death and FAS-ligand-mediated apoptosis of T cells. The finding that TIPE2 binds caspase-8, an apoptosis initiator and a regulator NF-κB, indicates that TIPE2 might influence immunoreceptor signalling pathways and apoptosis, in part, through this physical interaction.

B-cell signalling

Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Amin, R. H. & Schlissel, M. S. Nature Immunol. 11 May 2008 (doi:10.1038/ni.1612)

The authors sought to determine what factors were involved in the regulation of recombination-activating gene 1 (RAG1) and RAG2 during B-cell development. Using a retroviral cDNA library screen, they found that the stress-regulated protein GADD45a induced Rag1 transcription through the activation of the kinase p38 and the transcription factor FOXO1, and that FOXO1 could bind directly to the Rag locus. Further analysis showed that FOXO1 also regulated Rag1 transcription in developing primary B cells and 'knockdown' of FOXO1 expression resulted in reduced Rag1 and Rag2 transcription in a model of receptor editing. In addition, they found that the suppression of Rag1 transcription in both pro-B cells and immature B cells, induced by interleukin-7 receptor and B-cell receptor signalling, respectively, was through, in part, the PI3K- and AKT-signalling pathway. Inhibition of AKT increased Rag1 transcription and decreased FOXO1 phosphorylation.

NKT cells

Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice. Kim, S. et al. J. Clin. Invest. 1 May 2008 (doi:10.1172/JCI33071)

It is known that repeated stimulation of invariant natural killer T (iNKT) cells with the activating ligand α-galactosylceramide (α-GalCer) results in iNKT-cell anergy. Microorganisms can also activate iNKT cells, so Kim et al. examined the effect of prior exposure to bacteria on α-GalCer-mediated activation of iNKT cells. They found that iNKT cells in mice that were exposed to α-GalCer following bacterial infection were hyporesponsive and could not induce the expression of CD86 or CD69 by B cells and dendritic cells or induce interferon-γ production by NK cells. The therapeutic potential of α-GalCer might be compromised in infected individuals, as α-GalCer was less effective at inhibiting the development of tumour metastases or experimental autoimmune encephalomyelitis in mice pre-treated with bacteria.