Abstract
IL-22 is a member of the IL-10 cytokine family involved in host protection against extracellular pathogens, by promoting epithelial cell regeneration and barrier functions. Dysregulation of IL-22 production has also frequently been observed in acute respiratory distress syndrome (ARDS) and several chronic inflammatory and autoimmune diseases. We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. Here we characterized the role of CD28 autonomous signaling in regulating IL-22 expression in human CD4+ T cells. We show that CD28 stimulation in the absence of TCR strongly up-regulates IL-22 gene expression and secretion. As recently observed for IL-17A, we also found that CD28-mediated regulation of IL-22 transcription requires the cooperative activities of both IL-6-activated STAT3 and RelA/NF-κB transcription factors. CD28-mediated IL-22 production also promotes the barrier functions of epithelial cells by inducing mucin and metalloproteases expression. Finally, by using specific inhibitory drugs, we also identified CD28-associated class 1A phosphatidylinositol 3-kinase (PI3K) as a pivotal mediator of CD28-mediated IL-22 expression and IL-22–dependent epithelial cell barrier functions.
Highlights
IL-22 has been discovered in 2000 as a member of the IL-10 family that affects the functions of several non-hematopoietic cells, such as epithelial cells, keratinocytes, and hepatocytes [1]
In order to verify whether CD28-induced IL-22 expression was effective in healthy donors (HD) and clarify the molecular basis of this activity, we performed a kinetic analysis of IL-22 gene expression by stimulating human CD4+ T cells from HD with an agonistic anti-CD28 Ab (CD28.2) binding the same epitope recognized by B7 molecules [40] or anti-CD3 (UCHT1) or anti-CD3 plus anti-CD28 Abs
In mouse T cells, IL-22 is mainly regarded as a Th17 cytokine [41, 55, 56], whereas in human CD4+ T cells IL-22 expression often does not correlate with the expression of IL-17 or the master transcriptional regulator of Th17 cells retinoic acid receptor-related orphan nuclear receptor gt (RORgt) [57, 58]
Summary
IL-22 has been discovered in 2000 as a member of the IL-10 family that affects the functions of several non-hematopoietic cells, such as epithelial cells, keratinocytes, and hepatocytes [1]. IL-22 is mainly produced by Th17 cells, a subset of CD4+ T helper (Th) cells that regulate efficient immune defense against extracellular pathogens [2] and by a unique CD4+ Th cell subset, named Th22 [3,4,5]. A novel severe acute respiratory syndrome-related coronavirus 2 (SARSCov2) has been identified as the etiological agent of COVID-19 [16], a respiratory pandemic disease that, in several patients, causes ARDS associated with high levels of pro-inflammatory cytokines [17] including Th17 cytokines such as IL-22, IL-17, and IL-6 [18, 19]. The identification of stimulatory molecules and associated signaling pathways regulating and/or amplifying IL-22 production may provide new insight into immune defense against pathogens and novel therapeutic targets for inflammatory and autoimmune diseases
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