Vitamin A is a multifunctional vitamin implicated in a wide range of biological processes. Its control over the immune system and functions are perhaps the most pleiotropic not only for development but also for the functional fate of almost every cell involved in protective or regulatory adaptive or innate immunity. This is especially key at the intestinal border, where dietary vitamin A is first absorbed. Most effects of vitamin A are exerted by its metabolite, retinoic acid (RA), which through ligation of nuclear receptors controls transcriptional expression of RA target genes. In addition to this canonical function, RA and RA receptors (RARs), either as ligand-receptor or separately, play extranuclear, nongenomic roles that greatly expand the multiple mechanisms employed for their numerous and paradoxical functions that ultimately link environmental sensing with immune cell fate. This review discusses RA and RARs and their complex roles in innate and adaptive immunity.

The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response1. HVEM was recently reported as a colitis risk locus in patients2, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM3, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection4–6, a mouse model for enteropathogenic Escherichia coli infection, Hvem−/− mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection9, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.

Summary Coreceptor CD4 and CD8αβ double negative (DN) TCRαβ+ intraepithelial T cells, although numerous, have been greatly overlooked and their contribution to the immune response is not known. Here we used T cell receptor (TCR) sequencing of single cells combined with retrogenic expression of TCRs, to study the fate and the major histocompatibility complex (MHC) restriction of DN TCRαβ+ intraepithelial T cells. The data show that commitment of thymic precursors to the DN TCRαβ+ lineage is imprinted by their TCR specificity. Moreover, the TCRs they express display a diverse and unusual pattern of MHC restriction that is non-overlapping with that of CD4+ or CD8αβ+ T cells, indicating that they sense antigens that are not recognized by the conventional T cell subsets. The new insights indicate that DN TCRαβ+ T cells form a third lineage of TCRαβ T lymphocytes expressing a variable TCR repertoire, which serve non-redundant immune functions.

Dendritic cells (DCs) play an important role in bridging innate and adaptive immunity. These APCs have the ability to recognize specific molecular signatures of pathogens through TLRs. In particular, the intracellular TLR7 and TLR8, mediating the recognition of ssRNA by DCs, play a major role in the immune response during viral infection. Although differences have been identified between TLR7 and TLR8, in terms of cellular expression and functions, the signaling pathways that lead to DC maturation following TLR7 or TLR8 engagement are largely unknown. We compared the signaling pathways involved in human CD34-DC maturation induced by agonists selective for TLR7 (imiquimod) or TLR8 (3M002). TLR7 and TLR8 activation up-regulated CCR7, CD40, CD86, and CD83 expression and IL-6 and IL-12p40 production. However, only TLR8 activation led to IL-12p70 production and il-12p35 mRNA expression. We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. However, although p38MAPK participated in the up-regulation of maturation markers in response to TLR7 activation, this kinase exerted an inhibitory effect on CD40 expression and IL-12 production in TLR8-stimulated DCs. We also showed that the Jak/STAT signaling pathway was involved in CD40 expression and cytokine production in TLR7-stimulated DCs but negatively regulated CD83 expression and cytokine secretion in DCs activated through TLR8. This study showed that TLR7 and TLR8 activate similar signaling pathways that play different roles in DC maturation, depending on which TLR is triggered.