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TGF-β-activated kinase 1 (TAK1) is known to play vital roles for innate and adaptive immunity; however, little is known about its potential role in limiting biological responses such as inflammation. In this study, we report that macrophage TAK1 participates in negatively regulating inflammation by restraining proinflammatory cell death. Macrophages from TAK1-deficient mice underwent cell death in response to LPS and poly(I:C), which took place in a manner dependent on TLR/TRIF-induced active Caspase8-mediated cleavage of gasdermin D, known as an executioner of pyroptosis. Likewise, TNF-α induced Caspase8-dependent gasdermin D processing following cell death in TAK1-deficient macrophages. Importantly, we demonstrated that this type of proinflammatory macrophage death is linked to susceptibility to septic shock in mice lacking TAK1 in macrophages in a TNF-α-independent fashion. Taken together, our data revealed that TAK1 acts as a signaling checkpoint to protect macrophages from unique proinflammatory cell death, ensuring the maintenance of innate immune homeostasis. [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]