Constitutive Type 1 Interferon Selectively Promotes STAT1-associated IL-10 Production by Human Intestinal T Cells in Health, but not IBD

Immunoregulatory roles for Type 1 Interferon (T1IFN) are increasingly recognised. T1IFN signalling ameliorates murine colitis by promoting regulatory T cell function. In humans, T1IFN has been used as a treatment of IBD with variable efficacy. To test the hypothesis that T1IFN contributes to immune regulation in the human intestine, we assessed its expression in the colon, effect on Signal Transduction and Activator of Transcription 1 (STAT1) signalling and impact on the function of human intestinal T cells. Type 1 IFN (IFNβ) was detected in the human colon by immunohistochemistry and T cells isolated from colonic biopsies responded to exogenous T1IFN by phosphorylation of (p)STAT1. Colonic T cells from IBD patients showed increased responsiveness to T1IFN by more pSTAT1⁺ T cells and enhanced expression of Interferon Stimulated Genes (MxA and 2’5’OAS). The effect of endogenous T1IFN was assessed by addition of neutralising anti-IFNβ antibody to ex vivo biopsy organ cultures. In controls, neutralisation of IFNβ reduced the frequency of IL-10 producing T cells, and increased IFNγ production. In contrast, neutralisation of IFNβ in cultures of IBD biopsies had no selective effect on IL-10 but increased the frequency of T cells producing a broad range of cytokines (IL-10, IFNg, TNFa and IL-17). Therefore T1IFN, present in the human gut, impacts upon STAT1 signalling and T cell function differently in health and in IBD.  In health, selective promotion of a regulatory IL-10 response in T cells to T1IFN may be important in maintaining mucosal integrity in response to viral or other pathogens.