Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

Abstract

Under physiological conditions the gut associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens1,2. A notable counter-example is celiac disease, where genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T cell and antibody responses against dietary gluten, a protein present in wheat3. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, was shown to play a critical role in the induction of intestinal regulatory responses4–6. We found that in conjunction with IL-15, a cytokine greatly upregulated in the gut of celiac disease patients, retinoic acid rapidly activated dendritic cells to induce JNK phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings unveil an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.

Response to “Disparity between vitamin A-induced Th1-dependent oral tolerance in newborn mice and vitamin A-induced atopic sensitization in Guinean girls”

“…Vitamin A metabolite retinoic acid was shown to foster inflammatory immune response to dietary antigens given to mice exhibiting gut mucosal inflammation instead of the expected regulatory immune response observed in non-inflammatory conditions. 5 Our hypothesis is supported by epidemiological studies performed in high-income countries, which either showed an inverse correlation between retinol levels in the first months of life and risk of atopy or no significant association, but none of them showed increased risk (reviewed in ref. 6).…”

Dietary gluten triggers concomitant activation of CD4 + and CD8 + αβ T cells and γδ T cells in celiac disease

“…The presence of inflammation has long been postulated to promote the loss of tolerance, and prevailing models of CD pathogenesis propose that IELs are activated as a result of inflammation that is initiated by gluten-specific CD4 + cells. The inflammatory cytokine IL-15 is up-regulated within celiac intestinal mucosa, and has been implicated in promoting inflammation through diverse means, including impairing regulatory T-cell generation promoting NK-like function of CD8 + IELs, and enabling the expansion of IELs (9,33). CD8 + IELs have been shown to demonstrate cytotoxicity through stimulation by IL-15 and activation through NK receptors including CD94 and NKG2D (9,34).…”

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

“…Moreover, JU may act on more than 10 pathways, which may contribute to the pure synergistic mechanism (Supplement Table 2). Some of these new pathways were involved in inflammatory immunity (IL-18 Signaling, Actin Cytoskeleton Signaling, Glucocorticoid Receptor Signaling, Lymphotoxin B Receptor Signaling, and IL-15 Signaling [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] [69][70][71][72][73][74][75][76][77] . Therefore, we propose that the pure synergistic mechanism is focused on inflammation, immune responses, apoptosis, and nervous system development ( Figure 6).…”