Abstract
How T cells differentiate in the neonate may critically determine the ability of the infant to cope with infections, respond to vaccines and avert allergies. Previously, we found that naïve cord blood CD4+ T cells differentiated toward an IL-4-expressing phenotype when activated in the presence of TGF-β and monocyte-derived inflammatory cytokines, the latter are more highly secreted by infants who developed food allergy. Here, we show that in the absence of IL-2 or IL-12, naïve cord blood CD8+ T cells have a natural propensity to differentiate into IL-4-producing non-classic TC2 cells when they are activated alone, or in the presence of TGF-β and/or inflammatory cytokines. Mechanistically, non-classic TC2 development is associated with decreased expression of IL-2 receptor alpha (CD25) and glycolysis, and increased fatty acid metabolism and caspase-dependent cell death. Consequently, the short chain fatty acid, sodium propionate (NaPo), enhanced IL-4 expression, but exogenous IL-2 or pan-caspase inhibition prevented IL-4 expression. In children with endoscopically and histologically confirmed non-inflammatory bowel disease and non-infectious pediatric idiopathic colitis, the presence of TGF-β, NaPo, and IL-1β or TNF-α promoted TC2 differentiation in vitro. In vivo, colonic mucosa of children with colitis had significantly increased expression of IL-4 in CD8+ T cells compared with controls. In addition, activated caspase-3 and IL-4 were co-expressed in CD8+ T cells in the colonic mucosa of children with colitis. Thus, in the context of colonic inflammation and limited IL-2 signaling, CD8+ T cells differentiate into non-classic TC2 that may contribute to the pathology of inflammatory/allergic diseases in children.
Highlights
Differentiation of naïve CD4+ T cells into functionally distinct helper T cell (TH) lineages such as TH1 (IFN-γ), TH2 (IL-4), TH17 (IL-17), and TFH (IL-21) cells and induced regulatory T cells that express FOXP3 is shaped by the cytokine environment [1]
We reported that TGF-β and inflammatory cytokines, the latter secreted in higher amounts by cord blood monocytes from infants who developed food allergy, suppressed IL-2 expression by human cord blood CD4+ T cells and promoted a non-classical IL-4 TH2-type phenotype in naïve CD4+ T cells and naïve natural regulatory CD4+ T cells [13]
We found that in the absence of IL-2 or IL-12, naïve cord blood CD8+ T cells have a natural propensity of differentiating into IL-4-producing non-classic TC2 cells, associated with decreased glycolysis and increased fatty acid metabolism and caspase-dependent cell death
Summary
Differentiation of naïve CD4+ T cells into functionally distinct helper T cell (TH) lineages such as TH1 (IFN-γ), TH2 (IL-4), TH17 (IL-17), and TFH (IL-21) cells and induced regulatory T cells (iTreg) that express FOXP3 is shaped by the cytokine environment [1] This reflects the nature of local tissues (e.g., mucosal or systemic lymphoid), as well as innate immune inflammatory responses to pathogens and other stimuli [2]. We reported that TGF-β and inflammatory cytokines, the latter secreted in higher amounts by cord blood monocytes from infants who developed food allergy, suppressed IL-2 expression by human cord blood CD4+ T cells and promoted a non-classical IL-4 TH2-type phenotype in naïve CD4+ T cells and naïve natural regulatory CD4+ T cells [13] This prompted us to investigate the differentiation of naïve cord blood CD8+ T cells in the presence of inflammatory cytokines. Similar cells were identified in situ in the colon of children with endoscopically and histologically confirmed non-inflammatory bowel disease (IBD) and non-infectious pediatric idiopathic colitis (PIC)
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