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Transforming growth factor (TGF)-β-activating kinase 1 (TAK1) is critical for Toll-like receptor- and tumor necrosis factor-mediated cellular responses. In B cells, TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs), but not nuclear factor-κB (NF-κB), in antigen receptor signaling. In this study, we generate T cell-specific TAK1-deficient (LckCre/+Tak1flox/flox) mice and show that TAK1 is indispensable for the maintenance of peripheral CD4 and CD8 T cells. In thymocytes, TAK1 is essential for TCR-mediated activation of both NF-κB and MAPKs. Additionally, LckCre/+Tak1flox/flox mice developed colitis as they aged. In these mice, accumulations of activated/memory T cells as well as B cells were observed. Development of regulatory T (Treg) cells in thymus was abrogated in LckCre/+Tak1flox/flox mice, suggesting that the loss of Treg cells is the cause of the disease. Together, the results show that TAK1, by controlling the generation of central Treg cells, is important for preventing spontaneously developing colitis. [ABSTRACT FROM AUTHOR]

Polyubiquitination of proteins plays a critical role in the activation of immune cells. K63-linked polyubiquitin-binding proteins TGF-β-activated kinase 1 (TAK1)-binding protein (TAB)2 and TAB3 are implicated in NF-κB signaling via TAK1 activation. However, TAB2 alone is dispensable for NF-κB activation in embryonic fibroblasts, and the functional roles of TAB2 and TAB3 in immune cells has yet to be clarified. In this study, we demonstrate that TAB2 and TAB3 are essential for B cell activation leading to Ag-specific Ab responses, as well as B-1 and marginal zone B cell development. TAB2 and TAB3 are critical for the activation of MAPKs, especially ERK, but not NF-κB, in response to TLR and CD40 stimulation in B cells. Surprisingly, TAB2 and TAB3 are dispensable for TAK1 activation in B cells, indicating that TAB2 and TAB3 activate MAPKs via a pathway independent of TAK1. In contrast to B cells, macrophages lacking TAB2 and TAB3 did not show any defects in the cytokine production and the signaling pathway in response to TLR stimulation. Furthermore, TAB2 and TAB3 were dispensable for TNF-induced cytokine production in embryonic fibroblasts. Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-κB axis. [ABSTRACT FROM AUTHOR]

NK cell receptors (NKRs) such as NK1.1, NKG2D, and Ly49s are expressed on subsets of CDld-independent memory phenotype CD8+ and CD4-CD8- T cells. However, the mechanism for the generation and functions of these NKR+ T cells remained elusive. In this study, we found that CDld-independent Ly49+ T cells were reduced severely in the spleen, bone marrow, and liver, but not thymus, in mice doubly deficient for IFN regulatory factor-2 (IRF-2) and CD Id, in which the overall memory phenotype T cell population was contrastingly enlarged. Because a large fraction of Ly49+ T cells coexpressed NK1.1 or NKG2D, the reduction of Ly49+ T cells resulted indirectly in underrepresentation of NK1.1+ or NKG2D+ cells. Ly49+ T cell deficiency was observed in IRF-2-/- mice additionally lacking IFN-α/βR a-chain (IFNARl) as severely as in IRF-2-/- mice, arguing against the involvement of the accelerated IFN-α/β signals due to IRF-2 deficiency. Rather, mice lacking IFN-α/βR alone also exhibited relatively milder Ly49+ T cell reduction, and IL-2 could expand Ly49+ T cells from IFNARl-/-, but not from IRF-2-/-, spleen cells in vitro. These results together indicated that IRF-2 acted in Ly49+ T cell development in a manner distinct from that of IFN-α/β signals. The influence of IRF-2 deficiency on Ly49+ memory phenotype T cells observed in this study suggested a unique transcriptional program for this T cell population among other NKR+ T and memory phenotype T cells. [ABSTRACT FROM AUTHOR]

The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-I/Toll receptor family. Interestingly, the TLR4 gene has been localized to the same region to which the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR4. Macrophages and B cells from TLR4-deficient mice did not respond to LPS. All these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved among the IL-l/Toll receptor family. Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-κB. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response. [ABSTRACT FROM AUTHOR]

A switchlike response in nuclear factor-κB (NF-κB) activity implies the existence of a threshold in the NF-κB signaling module. We show that the CARD-containing WIAGUK protein 1 (CARMA1, also called CARD1D-TAK1 (MAP3K7)-inhibitor of NF-κB (IκB) kinase-β (IKKβ) module is a switch mechanism for NF-βB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKβ to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKβ target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-κB in single cells, suggesting that phosphorylation of this residue accounts for the feedback. [ABSTRACT FROM AUTHOR]