Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance

Abstract

Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.

GPR55 regulates intraepithelial lymphocyte migration dynamics and susceptibility to intestinal damage

“…A previous study showed that treatment of mice with anti-CD3 caused upregulation of IFN-inducible genes including Pkr and Usp18 within 3 hrs and this was suggested to reflect direct crosstalk between IELs and epithelial cells (38). In accord with the increased numbers of IELs and their increased overall association with the epithelial cells, anti-CD3 antibody treatment led to a stronger induction of Pkr and Usp18 in the intestine of GPR55 KO mice (Fig.…”

“…Anti-CD3 (25μg LEAF anti-CD3ε 2C11) was given i.p. and the small intestine (duodenum) harvested for RNA preparation as described (38). Animals were housed in a specific pathogen–free environment in the Laboratory Animal Research Center at the UCSF, and all experiments conformed to ethical principles and guidelines approved by the UCSF Institutional Animal Care and Use Committee.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…95 However, whether these properties are gut-specific or generally associated with T RM s isolated from other tissues awaits future clarification.…”

The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus

“…Strikingly, IFN-λ is uniquely responsible for control of early and persistent CR6 replication in the IECs of the colon [68,72]. Additionally, treatment with recombinant IFN-λ [72] or stimulation of IFN-λ production by intra-epithelial T cells [76] clears persistent MNV from the intestine. Conversely, IFN-α/β prevents systemic spread of CR6 and limits systemic replication of CW3 [72,77,78] (Figure 4A).…”