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.