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Chronic gut inflammation contributes to a higher risk of developing colorectal cancers (CRCs) in a person's lifetime. Interleukin-2 (IL-2), a pleiotropic cytokine, plays an unequivocal role in intestinal inflammation, as it is required for regulatory T cell-mediated gut immune tolerance. Exaggerated IL- 2 signaling, however, can promote inflammation by driving cytotoxic CD8 T-cell proliferation. The known cellular sources of intestinal IL-2 include CD4 T-cells and group-3 innate lymphoid cells. Published transcriptomic datasets revealed positive expression of IL-2 transcripts in intestinal epithelial cells (IECs). We demonstrated that IECs are novel producers of IL-2. IECs from mice with conditional knockout (cKO) of IL-2 exhibit reduced IL-2 mRNA and protein expression compared to their wild type (WT) counterparts. Epithelial IL-2 promotes colitis in mice, evidenced by WT mice developing more severe colitis compared to cKO mice following the administration of dextran sodium sulfate (DSS). Consistent with this, epithelial IL-2 was found to promote rectal adenomas in an azoxymethane (AOM)/DSS-induced CRC model. Immunophenotyping of WT vs cKO mice showed that epithelial IL-2 suppresses colonic CD4+CD8αα+ intraepithelial lymphocytes (IEL) and enhances TCRγδ CD8αα+ IEL numbers. Ongoing mechanistic experiments seek to understand how the immune cells of interest regulate epithelial IL-2 driven colitis and tumorigenesis. 537

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University of Florida / 2024

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