TLR7-Dependent Autoimmunity Remodels Intestinal Immune Cell Dissemination

Abstract

Intestinal immune cell dissemination has emerged as a fundamental mechanism of tissue-to-tissue immune communication that shapes systemic immunity, yet how this physiological process changes across different stages of systemic autoimmunity remains poorly understood. Here, using photoconversion, inducible and spontaneous models of TLR7-dependent autoimmunity, and microbiota perturbation, we define how autoimmunity reshapes intestinal immune dissemination. TLR7-dependent autoimmunity progressively suppresses dissemination in a tissue-dependent manner across gut-associated and systemic tissues while selectively reconfiguring the intestinal emigrant pool, characterized by reduced lymphocyte dissemination and increased representation of myeloid populations, particularly dendritic cells. This divergence is already evident in young TLR7-transgenic mice before detectable splenomegaly. Moreover, microbial regulation of intestinal dissemination depends on timing and inflammatory context, with antibiotic treatment during ongoing autoimmunity producing broader changes in intestinal immune dissemination. Together, our findings establish remodeling of physiological intestinal immune dissemination as an early feature of TLR7-dependent autoimmunity and reveal how chronic inflammation reshapes tissue-to-tissue immune communication.