Our early studies on TH17 cells revealed that they were most abundant in the intestinal lamina propria, and that they were absent in germ-free mice. This observation led us to identify segmented filamentous bacteria (SFB) as specific inducers of TH17 cells, highlighting the roles of commensal intestinal bacterial species in specifying unique programs of T cell differentiation locally in the gut. Moreover, intestinal bacteria also have distal effects, and can promote tissue-specific T cell-mediated autoimmune diseases as well as responses to cancer immunotherapy. A major thrust of our research program is aimed at understanding the local and systemic immune-modulatory effects of individual or communities of commensal bacterial species. Our studies encompass identification of human bacterial species and defined bacterial communities associated with beneficial or detrimental effects on host immunity, characterization of the bacterial products and their molecular targets in host cells, and mapping of downstream cellular interaction networks.  We are particularly interested in the roles of myeloid lineage cells and of ILCs in the induction of distinct functional subsets of CD4+ T cells and in the regulation of T cell homeostasis at mucosal sites, where commensal microorganisms must be distinguished from potentially harmful pathogenic ones. To do this, we have generated a series of genetically engineered mice and reagents to allow for monitoring of T cell responses specific for individual bacterial species. We chose Helicobacter hepaticus (H. hepaticus) as a model to investigate host interactions with pathobionts, which are commensal microbes that exert their pro-inflammatory potential only when host immune regulatory processes are compromised. Using tools that allow tracing of the fate of H. hepaticus-specific T cells, we found that healthy individuals host H. hepaticus without developing inflammatory disease by inducing microbe-specific RORgt+Foxp3+ regulatory T cells (iTreg), which prevent expansion of H. hepaticus-specific pathogenic TH17 cells. These findings suggest that this mechanism serves as a strategy for the microbe’s commensalism. In mice defective for these iTreg cells, expansion of pathogenic TH17 cells results in inflammatory bowel disease. These TH17 cells differ markedly from homeostatic TH17 cells, such as those induced by Segmented Filamentous Bacteria (SFB). SFB-specific TH17 cells are abundant in the healthy gut and protect the mucosa from pathogenic microbes without causing inflammation. SFB-specific TH17 cells isolated from both IL-10-sufficient and IL-10-deficient mice with colitis exhibited highly similar transcriptional profiles, which were distinct from those of H. hepaticus-specific TH17 cells from IL-10 deficient animals. Deciphering the differential regulation of these TH17 cells may open new avenues for therapeutic intervention in autoimmune diseases. We are therefore investigating how antigen-presenting cells and other cell types regulate the pathobiont-specific iTreg-TH17 axis as well as microbe-specific homeostatic TH17 and TH1 programs.

To characterize the cells and molecules required for commensal microbes to instruct the diverse T cell differentiation programs, we are combining live imaging, single cell transcriptomics/proteomics, and genetic approaches with in vitro reconstitution models. We have thus begun to map the downstream cellular interaction networks, composed of macrophages, dendritic cells and ILCs, that facilitate distinct immune responses by peripheral CD4+ T cells. Our early studies suggest that different migratory cells are required for priming SFB- versus H. hepaticus-specific T cells in the draining mesenteric lymph nodes.

Our goal is to develop tools to study the features of both the relevant commensal bacteria and of the host in the induction of distinct immune responses. Using bacteria that can be genetically manipulated, it will be possible to identify the gene products and metabolites that are critical for modulating host responses. We have focused on mechanisms by which secondary bile acids influence the differentiation of T cells, e.g. TH17 and Treg cells. In collaboration with the laboratory of Michael Fischbach (Stanford University), we found derivatives of lithocholic acid that either inhibit TH17 cell differentiation or enhance Treg cell differentiation. We are working on characterizing the molecular targets of these bile acids in collaboration with Jun Huh (Harvard Medical School). Since enzymes encoded by commensal bacteria convert liver-derived primary into secondary bile acids, we are striving to identify microbes that can be harnessed to elevate the levels of these metabolites, which may have favorable anti-inflammatory outcomes.

Related Publications:

• Hang, S., Paik, D., Devlin, A.S., Jamma, T., Lu, J., Ha, S., Nelson, B.N., Kelly, S.P., Wu, L., Zheng, Y., Rastinejad, F., Krout, M.R., Fischbach, M.A.*, Littman, D.R.*, & Huh, J.R.* (2018) Bile acid metabolites control Th17 and Treg cell differentiation.  Nature in press 2019. bioRxiv 465344

• Xu, M., Pokrovskii, M., Ding, Y., Yi, R., Au, C., Galan, C., Bonneau, R., & Littman, D.R. (2018) c-Maf-dependent regulatory T cells mediate immunological tolerance to intestinal microbiota.  Nature, 554, 373-77. PMID: 29414937

• Honda, K & Littman, D. R. (2016).  The microbiota in adaptive immune homeostasis and disease.  Nature. 535, 75-84. PMID: 27383982

• Yang, Y., Torchinsky, M.B., Gobert, M., Xiong, H., Xu, M., Linehan, J.L., Alonzo, F., Ng, C., Chen, A., Lin, X., Sczesnak, A., Liao, J.J., Torres, V.J., Jenkins, M.K., Lafaille, J.J., Littman, D.R. (2014) Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152-6. PMID: 24739972