Inducible Colonic M Cells Are Dependent on TNFR2 but Not Ltßr, Identifying Distinct Signalling Requirements for Constitutive Versus Inducible M Cells.

BACKGROUND AND AIMS: M cells associated with organised lymphoid tissues such as intestinal Peyer's patches provide surveillance of the intestinal lumen. Inflammation or infection in the colon can induce an M cell population associated with lymphoid infiltrates; paradoxically, induction is dependent on the inflammatory cytokine tumour necrosis factor [TNF]-α. Anti-TNFα blockade is an important therapeutic in inflammatory bowel disease, so understanding the effects of TNFα signalling is important in refining therapeutics. METHODS: To dissect pro-inflammatory signals from M cell inductive signals, we used confocal microscopy image analysis to assess requirements for specific cytokine receptor signals using TNF receptor 1 [TNFR1] and 2 [TNFR2] knockouts [ko] back-crossed to the PGRP-S-dsRed transgene; separate groups were treated with soluble lymphotoxin ß receptor [sLTßR] to block LTßR signalling. All groups were treated with dextran sodium sulphate [DSS] to induce colitis. RESULTS: Deficiency of TNFR1 or TNFR2 did not prevent DSS-induced inflammation nor induction of stromal cell expression of receptor activator of nuclear factor kappa-B ligand [RANKL], but absence of TNFR2 prevented M cell induction. LTßR blockade had no effect on M cell induction, but it appeared to reduce RANKL induction below adjacent M cells. CONCLUSIONS: TNFR2 is required for inflammation-inducible M cells, indicating that constitutive versus inflammation-inducible M cells depend on different triggers. The inducible M cell dependence on TNFR2 suggests that this specific subset is dependent on TNFα in addition to a presumed requirement for RANKL. Since inducible M cell function will influence immune responses, selective blockade of TNFα may affect colonic inflammation.

Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations.

Memory T helper cells (Th cells) play an important role in host defense against pathogens but also contribute to the pathogenesis of inflammatory disorders. We found that a soluble decoy lymphotoxin ß receptor (LT-ßR)-Fc, which can block tumor necrosis factor (TNF)-related ligands LIGHT (TNFSF14) and LT-αß binding to the herpesvirus entry mediator (HVEM) and the LT-ßR, inhibited the accumulation of memory Th2 cells after antigen encounter and correspondingly reduced inflammatory responses in vivo. Showing that this was a function of the receptor for LIGHT, antigen-specific memory CD4 T cells deficient in HVEM were also unable to persist, despite having a normal immediate response to recall antigen. HVEM(-/-) memory Th2 cells displayed reduced activity of PKB (protein kinase B; Akt), and constitutively active Akt rescued their survival and restored strong inflammation after antigen rechallenge. This was not restricted to Th2 memory cells as HVEM-deficient Th1 memory cells were also impaired in surviving after encounter with recall antigen. Furthermore, the absence of LIGHT on T cells recapitulated the defect seen with the absence of HVEM, suggesting that activated T cells communicate through LIGHT-HVEM interactions. Collectively, our results demonstrate a critical role of HVEM signals in the persistence of large pools of memory CD4 T cells.