Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis

INTRODUCTION Although commensal microbes populate our barrier surfaces without causing obvious disease, they nonetheless modulate host physiology and immunity. Commensal bacteria can regulate host T cell differentiation and function, and a large fraction of mucosal tissue-resident T cells are thought to recognize commensal antigens, which triggers the T cells’ participation in the maintenance of mucosal homeostasis. Therefore, the mechanisms by which commensal antigens or other microbiota-derived immune mediators are acquired and processed to activate specific types of host T cells are of substantial interest. Understanding commensal-host communication and commensal antigen acquisition is crucial for understanding the mechanisms of tissue homeostasis and for the design of alternative strategies for specific regulation of mucosal health and pathologies. RATIONALE Host-microbe interactions at the cellular level have been almost exclusively studied in the context of invasive pathogens. Our study explored whether noninvasive commensal microbes may possess previously unappreciated modes of antigen acquisition or communication with the host for maintenance of mucosal T cell homeostasis. RESULTS We examined the interaction of segmented filamentous bacteria (SFB), well-characterized T helper 17 (T H 17) cell–inducing epithelium-associated commensal microbes, with intestinal epithelial cells (IECs) by means of electron tomography. SFB were not phagocytosed by IECs and did not penetrate the IEC cytosol. SFB and IEC communicated through the generation of endocytic vesicles at the tip of the SFB-IEC synapse. The vesicles were released into the host IEC and contained an SFB cell wall–associated protein, which is a known immunodominant T cell antigen for the generation of mucosal T H 17 cells. Endocytic vesicles were present in virtually every SFB-IEC synapse in healthy animals, suggesting a highly dynamic process that occurs at steady state. SFB antigenic proteins were transferred through this process inside IECs and shuttled throughout the IEC endosomal-lysosomal network. Mechanistically, the endocytic process was clathrin-independent but dependent on dynamin and the actin regulator cell division control protein 42 homolog (CDC42). Chemical inhibition of CDC42 activity in vivo led to disruption of the endocytosis. Genetic deletion of CDC42 in IECs resulted in disruption of endocytosis induced by SFB, loss of transfer of antigenic proteins inside IECs, and substantial decrease in the activation of SFB-specific CD4 T cells and SFB-induced T H 17 cell differentiation. An examination of a few other epithelium-associated or T H 17 cell–inducing intestinal microbes showed dissimilar interactions with IECs, and therefore, SFB currently are the first and only example of this process. CONCLUSION Our results reveal a mechanism of interaction between a commensal microbe and the host that directs transfer of microbial proteins inside host cells. They also describe a previously unappreciated pathway for antigen acquisition from luminal commensal bacteria through IECs. Our results underscore that the study of the interactions of key individual commensal microbes with the host may uncover unappreciated biological pathways. Targeting such pathways may allow for ways to specifically regulate commensal versus pathogenic interactions, regulate the immunomodulatory effects of individual members of the gut microbiota, or design alternative strategies for mucosal vaccination.