Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20

Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive immune responses when combating microbial infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show that MyD88-dependent TLR signals drive the spontaneous T cell and myeloid cell activation, cachexia, and premature lethality seen in A20-deficient mice. We have used broad spectrum antibiotics to demonstrate that these constitutive TLR signals are driven by commensal intestinal flora. A20 restricts TLR signals by restricting ubiquitylation of the E3 ligase tumor necrosis factor receptor–associated factor 6. These results reveal both the severe proinflammatory pathophysiology that can arise from homeostatic TLR signals as well as the critical role of A20 in restricting these signals in vivo. In addition, A20 restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain–containing adaptor inducing interferon (IFN) β–dependent nuclear factor κB signals but not IFN response factor 3 signaling. These findings provide novel insights into how physiological TLR signals are regulated

Gut Cryptopatches Direct Evidence of Extrathymic Anatomical Sites for Intestinal T Lymphopoiesis

AbstractAthymic cytokine receptor γ chain mutant mice that lack the thymus, Peyer's patches, cryptopatches (CP), and intestinal T cells were reconstituted with wild-type bone marrow cells. Bone marrow–derived TCR− intraepithelial lymphocytes (IEL) first appeared within villous epithelia of small intestine overlying the regenerated CP, and these TCR− IEL subsequently emerged throughout the epithelia. Thereafter, TCR+ IEL increased to a comparable number to that in athymic mice and consisted of TCRγδ and TCRαβ IEL. In gut-associated lymphoid tissues of wild-type mice, only CP harbored a large population of c-kithighIL-7R+CD44+Thy-1+/−CD4+/−CD25low/−αEβ7−Lin− (Lin, lineage markers) lymphocytes that included cells expressing germline but not rearranged TCRγ and TCRβ gene transcripts. These findings provide direct evidence that gut CP develop progenitor T cells for extrathymic IEL descendants