Tofacitinib ameliorates Campylobacter-induced intestinal pathology by suppressing IFNγ producing ILCs and T cells.

Patients with autoimmune diseases are more susceptible to foodborne infections, which can be exacerbated by immunosuppressive therapy. Tofacitinib, a JAK/STAT pathway inhibitor, was recently approved for the treatment of ulcerative colitis, yet its effects on the pathogenesis of intestinal infections remain unclear. Here, we examined the impact of oral tofacitinib treatment in a mouse model of Campylobacter jejuni (C. jejuni) infection. Our results show that early tofacitinib administration attenuates intestinal pathology without affecting bacterial colonization. Specifically, tofacitinib suppressed CXCL1, CXCL2, CCL2 chemokine expression by intestinal epithelial cells, limiting recruitment of monocytes and neutrophils to the gut. In addition, JAK/STAT inhibition reduced IFNγ-producing innate lymphoid cells (ILCs) and T cells in the gut. Furthermore, tofacitinib suppressed IFNγ production and ameliorated intestinal disease in humanized mice. Cell-fate mapping revealed that tofacitinib predominantly inhibited IFNγ production by NK1.1 ILCs derived from NKp46 progenitors and reduced NK1.1 ILC proliferation without affecting ILC3 to ILC1 plasticity. Notably, tofacitinib ameliorated intestinal disease even in the absence of T cells. These findings suggest that tofacitinib alleviates C. jejuni-induced colitis by reducing proinflammatory cytokine production by monocytes/macrophages/epithelial cells and suppressing IFNγ secretion by ILCs and T cells, while preserving antibacterial defenses.