Expansion of human regulatory T cells protects humanized mice from experimental colitis

Many autoimmune and inflammatory disorders result from failure to establish or maintain central or peripheral tolerance and some have been attributed to altered regulatory T cell (Treg) number or function. Accordingly, many studies have focused on technologies to expand or promote Treg development/function. Here, we have developed humanized murine systems to assess directly in vivo technologies to expand Tregs. Low-dose IL-2 in humans has been shown to be an effective therapeutic strategy for Treg expansion in vivo for the treatment of chronic graft vs. host disease and HCV-induced vasculitis. However, the use of this modality for Treg expansion in the intestinal compartment to suppress colitis has not been evaluated. To test this approach, we generated immunodeficient mice that lack murine major histocompatibility complex II and instead express human HLADR1 and reconstituted these mice with human CD4⁺ T cells. Mice treated with TNBS developed weight loss, colitis, with the human T cells recovered from the colonic lamina propria expressing increased TNF and IFNg. Administration of low-dose IL-2 prior to TNBS was protective against TNBS-induced weight loss and colitis development. We also showed in this humanized system that activation of the aryl hydrocarbon receptor using the agonist ITE expands human regulatory T cells and protects against TNBS-induced colitis. These data demonstrate that human CD4⁺ T cells can promote colitis development in a humanized murine system and can serve as a pre-clinical model in which to evaluate immunomodulators or novel therapeutics aimed at promoting intestinal immune homeostasis.