Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis

Abstract

Innate immunity is maintained in part by antigen presenting cells (APCs) including dendritic cells, macrophages, and B cells. APCs interact with T cells to link innate and adaptive immune responses. By displaying bacterial and tumorigenic antigens on their surface via major histocompatibility complexes, APCs can directly influence the differentiation of T cells. Likewise, T cell activation, differentiation, and effector functions are modulated by APCs utilizing multiple mechanisms. The objective of this review is to describe how APCs interact with and influence the activation of T cells to maintain innate immunity during exposure to microbial infection and malignant cells. How bacteria and cancer cells take advantage of some of these interactions for their own benefit will also be discussed. While this review will cover a broad range of topics, a general focus will be held around pathogens, cancers, and interactions that typically occur within the gastrointestinal tract.

Keywords: APC; CRC; PAMP; SCFA; SFB; TLR.

Figure 1

Overview of innate immune interactions under homeostasis and dysbiosis. In healthy individuals, the commensal microbiota secretes products, including SCFAs such as butyrate, that act on DCs to maintain a commensal-tolerant immune system. The presence of commensal microbes has also been associated with an increased presence of T_h17 cells. Also, ILCs secrete cytokines to alter T cell function to maintain homeostasis. When dysbiosis is induced by bacterial pathogens such as S. Typhimurium, microbiota composition changes and mucus secretion increases. S. Typhimurium infection occurs via transcytosis by M cells into Peyer's patches where the bacterium can travel through lymphatic vessels to the MLN. To mount an immune response, S. Typhimurium antigens such as flagellin monomers are detected by TLR5 of DCs. DCs then produce IL-23 which promotes the release of IL-17 by memory T cells. IL-17 stimulates the differentiation of naïve CD4⁺ T cells into T_h17 cells. Likewise, TLR9 and NOD2 receptors are activated within Paneth cells to upregulate the secretion of AMPs.

Figure 2

CRC altered microbiota-dependent innate immune signaling facilitates tumorigenesis. The intestinal microbiota changes with the progression of CRC. For instance, increased levels of F. nucleatum have been associated with increased severity of CRC. CRC cells also display a “leaky” epithelial layer which allows for the entrance of microbial products into the tumor microenvironment. These products activate TLR signaling by DCs. IL-23 is then secreted by DCs to promote the secretion of IL-17A by T_h17 cells. IL-17A, in turn, is associated with angiogenesis.