Immune regulation via the gut microbiota & lymphatic cells
The microbiota plays an essential role in the immune system maturation and homeostasis since GALT maturation, T-cell activation, and plasma cell recruitment are all dependent on the microbiota-derived signals30,64,66. Immune cells in the intestine can be associated with two different functional sites: inductive sites (Peyer’s patches, MLNs, and lymphoid follicles) and effector sites (lamina propria and epithelia)67. Studies have shown that germ-free mice with immature gut microbiotas are more susceptible to GI infection with pathogenic bacteria due to their smaller MLNs and lamina propria, and reduced levels of T-helper 17 (Th17) and IgA31,68-70. However, these abnormalities can be ameliorated with the normal microbiota colonization of the gut5. While the commensal bacteria boost the host’s digestive system efficiency, colonization with pathogens can lead to inflammation and sepsis71. Alterations in the hGM can cause IBDs (Fig. 2)72. The intricate interplay between the human immune system and the microbiota has led to the cultivation of the latter by the former for protective purposes, and the evolution of metabolic benefits for both73. Our immune system has evolved to maintain a balanced environment by “identifying commensal bacteria and distinguishing them” from the pathogenic ones. Pathogenic organisms are sensed by the pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs)74. PRR activation results in the induction of a cascade of pro-inflammatory responses as a result of the recognition of pathogen-associated molecular patterns (PAMPs)74. Pili, flagella, and peptidoglycans are examples of known PAMPs.
Mononuclear phagocytes residing in the lamina propria, such as macrophages and dendritic cells (DCs) can distinguish between beneficial and harmful bacteria. These phagocytes are hyporesponsive to TLR ligands from commensal bacteria, which prevents the production of immune responses like TNF or IL-65,75. However, these same innate immune cells produce pro-inflammatory cytokines such as pro-IL-1-β when exposed to harmful bacteria, which can in turn induce the production of IL1-β through the NLRC4 inflammasome, which does not rely on TLR signaling (Fig. 1F, Fig. 2F)76. In addition, commensal microbiota instructs the intestinal immune system to limit responses to luminal antigens by inhibiting the transport of bacteria from the lumen to the mesenteric lymph nodes77. In a dysbiotic environment, non-invasive bacteria are trafficked to the CD103+ DCs in the mesenteric lymph nodes by CX3CR1hi mononuclear phagocytes in a CCR7-dependent manner. This results in T-cell activation and increased IgA production due to a lack of commensal bacteria-induced Myd88 activation (Fig. 2C)77,78.
The commensal microbiota promotes the development of regulatory T cells that play an essential role in immune tolerance9,38. In the GI tract, antigen-presenting cells (APCs) process the bacterial antigens and then present them to aid in the naive CD4+ T-cell transformation to a Th2 cell (Fig. 1F)79. This process allows Th2 cells to secrete effector cytokines like IL-1379. Germ-free mice were shown to have a CD4+ T-cell imbalance with a Th2 bias80, and mono-colonization of these mice with the commensal bacterium B. fragilis can reestablish the Th1 and Th2 balance80. Paneth cells in the small intestine secrete α-defensins, an antimicrobial peptide, which are the predominant antibacterial factors against enteric pathogenic bacteria (Fig. 1D)80. Recognition of microbial-associated molecular patterns (MAMPs) is another important pathway for immune regulation in the gut as MAMP receptors are expressed by epithelial cells and activate signaling cascades that influence cytokine production, such as IL-10, as well as other immune signaling molecules38,60.