CD28 Autonomous Signaling Orchestrates IL-22 Expression and IL-22-Regulated Epithelial Barrier Functions in Human T Lymphocytes

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-kB 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.

Binding of Staphylococcal Enterotoxin B (SEB) to B7 Receptors Triggers TCR- and CD28-Mediated Inflammatory Signals in the Absence of MHC Class II Molecules

“…By contrast, the SLP-76 Y3F dominant-negative mutant did not affect SEB-induced activation of NF-kB (Figure 6E) that is mainly regulated by CD28 (18) and depends on the recruitment of distinct adaptor signalling complexes (20,21,31,45,(68)(69)(70)(71). Human CD28 is able to deliver TCR-independent signals by recruiting important signalling mediators, which leads to the activation of NF-kB (21,22,41,(71)(72)(73) and the expression of its target genes including pro-inflammatory cytokine and chemokine genes (20,69,70,74,75). Accordingly, CD28 engagement by B7.1 strongly upregulated NF-kB transcriptional activity also in the absence of the TCR (Figure 5B).…”

“…For instance, despite SLP-76 being a scaffold protein that regulates several TCR-activated signalling pathways (46,(48)(49)(50), it acts as a main regulator of the NF-AT signalling pathway by favouring the activation of PLCg1 (65) as well as the nuclear import of NF-AT and its transcriptional activity (66,67). By contrast, the SLP-76 Y3F dominant-negative mutant did not affect SEB-induced activation of NF-kB (Figure 6E) that is mainly regulated by CD28 (18) and depends on the recruitment of distinct adaptor signalling complexes (20,21,31,45,(68)(69)(70)(71). Human CD28 is able to deliver TCR-independent signals by recruiting important signalling mediators, which leads to the activation of NF-kB (21,22,41,(71)(72)(73) and the expression of its target genes including pro-inflammatory cytokine and chemokine genes (20,69,70,74,75).…”

IL‑22 alleviates the fibrosis of hepatic stellate cells via the inactivation of NLRP3 inflammasome signaling

“…Interleukin (IL)-22 was originally identified as an IL-10-related T cell-derived inducible factor ( 8 ). IL-22 is an actively secreted protein of 146 amino acids, which belongs to the IL-10 family of cytokines ( 9 , 10 ).…”

The Anti-Inflammatory Effect of Aptamin C on House Dust Mite Extract-Induced Inflammation in Keratinocytes via Regulation of IL-22 and GDNF Production

“…TARC is associated with chemotaxis of T cells, particularly Th2 cells, and is involved in the pathogenesis of skin inflammation in AD by enhancing migration of T cells into skin lesions [4,37]. Additionally, TARC production results from the interaction between IL-22 and its receptor on skin keratinocytes [6,12]. Because Aptamin C downregulates HDMinduced IL-22 production by T cells, as well as IL-22Rα expression by HaCaT, we assessed the effects of Aptamin C on TARC production.…”

“…TARC production is induced by the interaction between interleukin (IL)-22 and its receptor IL-22Rα, followed by migration of T cells into AD skin lesions. IL-22 is a proinflammatory cytokine produced mainly by CD4 + T cells and natural killer (NK) cells, but it also has anti-inflammatory functions [6][7][8]. IL-22 levels in the skin of AD patients is higher than that in controls, and its production is increased by HDM [9][10][11].…”