An expanding stage for commensal microbes in host immune regulation

Abstract

Gastrointestinal commensal microbiota is a concentrated mix of microbial life forms, including bacteria, fungi, archaea and viruses. These life forms are targets of host antimicrobial defense in order to establish a homeostatic symbiosis inside the host. However, they are also instrumental in shaping the functions of our immune system via a diverse set of communication mechanisms. In the gut, T helper 17, regulatory T and B cells are continuously tuned by specific microbial strains and metabolic processes. These cells in return help to establish a mutually beneficial exchange with the gut microbial contents. Imbalances in this symbiosis lead to dysregulations in the host's ability to control infections and the development of autoimmune diseases. In addition, the commensal microbiota has a significant and obligatory role in shaping both gut intrinsic and distal lymphoid organs, casting a large impact on the overall immune landscape in the host. This review discusses the major components of the microbial community in the gut and how its members collectively and individually exert regulatory roles in the host immune system and lymphoid structure development, as well as the functions of several major immune cell types.

Figure 1

Gut microbial environment impacts resident lymphocytes. In the steady state, gut microbial contents polarize and fine-tune several types of lymphocytes. The presence of bacterial strains such as segmented filamentous bacteria (SFB) drives B cells to produce IgA, likely assisted by RALDH⁺ dendritic cells. The resulting immunoglobulin A (IgA) restricts the otherwise unchecked expansion of several bacterial species. Treg cells are induced by Clostridia members and are also strongly linked to the availability of fermentation products such as short-chain fatty acids (SCFAs), while T helper 17 (TH17) cells are mostly driven by SFB and the high concentration of ATP in the intestinal lumen. In parallel to these events, gut microbial antigens are sampled by dendritic cells (DCs) and presented to various types of lymphocytes, leading to a complex balance of activation/inhibition and gut immune homeostasis.

Figure 2

Peripheral lymphoid volume and gut microbiota. Dendritic cells (DCs) entering secondary lymphoid organs (SLOs) is a critical event to maintaining the proper structure of lymph nodes (LNs). We have found that fungal species drive a group of CD103⁺CD11b⁺RALDH⁺ DCs to leave the gut and enter distal LNs. These fungi mediate the MAdCAM-1 to PNAd addressin profile switch to initiate the adult pattern of lymphocyte homing, resulting in SLO volume expansion. This switch gradually reduces the migration of these DCs to peripheral LNs. In the early weeks, lymphocytes circulating through these LNs are further routed back to the gut, a phenomenon that gradually disappears in the later weeks. The small presence of these DCs is critical to preventing structure attrition in adult LNs.