The Immune System in the Healthy Gut

The intestinal tract is bombarded with food, toxins and microbes. Somehow, our bodies are able to examine this mess and decide which of the substances you ingest are good and which ones are bad. The secret is in the immune system of the intestinal tract.

Small Intestine vs. Colon

The small intestine and the large intestine are very different in their function. Most of the nutrient absorption takes place in the small intestine, while the colon is specialized absorbing water. The small intestine is more acidic near the stomach than near the large intestine. For this reason, the amounts of bacteria that are found in the small intestine are much lower than what is found in the bacteria rich colon. Because the amount of bacteria is lower, the protective mucus layer is also much thinner than in the colon. The types of bacterial species are also different between the two organs as well, which has led scientists to believe that the immune function in each organ may also have a different function.

colon vs small intestine

Although the layers of tissue that make up the intestinal walls in the small intestine and colon are similar, the inner surface appears very different. Both have an exterior layer called the “serosa,” followed by two separate muscle layers that are responsible for the contraction of the intestine. These layers are then followed by the “submucosa,” which contains connective tissues and the “mucosa.” The mucosa forms the inner surface. In the small intestine, this area contains the cell-rich villi and crypts, while in the colon there are only crypts.

Epithelial cells of the mucosa form the villi and the crypts. These cells are the outermost layer of cells that interact with the intestinal lumen. Within this layer are also other types of cells including Goblet cells that are specialized for the production of mucus. Paneth cells, located in the crypts that are designed to produce anti-microbial peptides, and stem cells, which are responsible for renewing the epithelial layer cells. The epithelial layer is crucial to maintaining the barrier of the intestine and preventing the entrance of bacteria.

Peyer's patch
Red circle indicates a Peyer’s patch

Immunological Hot Spots of the Intestines

The mucosa is also where much of the immunological action happens. Both types of intestines contain lymphoid structures. In the small intestine there are Peyer’s patches (PPs), and colons have Colon patches (CPs). These structures are relatively large, extending from the mucosa into the submucosa. Another important location is lamina propria (LP). This is the space right under the epithelial cells, forming the interior of the villi and the areas between the crypts. The patches and LP are filled with immune cells.

Scientists use the term gut associated lymphoid tissue or GALT to describe the important immune structures associated with the intestinal tract. It includes the PPs of the small intestine, the CPs of the colon, the appendix and lymph nodes located in the mesentery tissues that hold the intestines together. The LP of the gut, while housing many immune cells, is not considered GALT. GALT includes only organized lymphoid structures of the gut.

Lamina Propria

Both the small intestinal and colonic LP have similar types of immune cells. When healthy, both have a wide variety of immune cells. One can find macrophages, T cells, dendritic cells (DCs), plasma cells and innate lymphoid cells (ILCs). These immune cells function similarly in both organs.

Each cell has its own task. Both macrophages and DCs are known to extend dendrites through the epithelial layer to fish out any microbes that have penetrated the mucus layer. Using pattern recognition receptors (PRRs), they can estimate the pathogenicity of what they engulf. While many will present their antigens to local T cells, some will travel via the lymphatics to the mesenteric lymph nodes (MLNs). The local T cells are generally of the effector/memory type. These are cells that have previously been stimulated and have expanded. They are capable of quickly moving into action as soon as they recognize a presented epitope. Plasma cells are also in the LP, and their job is to produce large amounts of protective secretory IgA (sIgA). The ILCs are similar to T cells, but they do not have adaptive receptors. Instead they use activating receptors and inhibiting receptors, which can interact with ligands expressed by epithelial cells. These cells are extremely capable of alerting others to danger by secreting a large number of cytokines that both alert and inform other cells. By performing their individual jobs, the immune cells work together to protect the barrier of the intestinal tract.

Peyer patches MHCII-GFP mouse
GFP expression on antigen-presenting cells shows the location of a Peyer’s patch in a mouse colon.

Peyer’s Patches and Colonic Patches

The function of the lymphoid structures is to educate the adaptive immune cells. Both types of patches contain T cells, B cells and dendritic cells. They function a lot like lymph nodes; they are places where T and B cells are stimulated to perform their effector functions. In the PPs, M cells, located on the surrounding epithelial layer, pump antigens from the lumen to the cells below. This provides the DCs with antigens to stimulate the neighboring T cells and, it also provides B cells with soluble antigens, which are needed for their development into mature B cells and plasma cells. It is believed that the PPs are one the main areas that induced regulatory T cells (Tregs) are formed. CPs, on the other hand, appear to be more attuned towards plasma cell production for protective sIgA. During periods of health the education that the adaptive immune response receives is mainly anti-inflammatory in nature and supports tolerance to intestinal flora and food.

Appendix

The appendix is actually full of lymphoid structures. The appendix, in humans, is a small, finger-like projection that extends below the cecum. It is considered a vestigial organ that is no longer really needed. Scientists hypothesize that it may have been a commensal microbe reservoir. However, that function appears to be fulfilled by the cecum, the part of the large intestine that hangs below the area where the small intestine exits into the large intestine. The cecum has colonic patches. It may be that the immune structures in the appendix are not really necessary.

Mesenteric Lymph Nodes

The MLNs function as an exterior lymphoid structure that support the adaptive immune response. It is supplied with antigens via fluid that drains to the connecting lymphatic vessels and by migrating DCs and macrophages. DCs are known to travel to here from both the LP and PPs. Precise studies have not been done to show if antigen-presenting cells travel from the colon LP or the CPs to the MLNs, although, it is very likely. In the mLN, T cells are activated and differentiated and B cells also differentiate to antibody-producing plasma cells. Like the PPs, during health, the focus of the adaptive cell education is on responses that are tolerant to intestinal microbiota and food antigens.

Many cells participate in maintaining health at the intestinal-lumen interface.
Many cells participate in maintaining health at the intestinal-lumen interface. ILCs: innate lymphoid cells, AMPs: anti-microbial peptides, sIgA: secretory IgA

Healthy Immune Interactions

Health in the digestive tract is maintained by the constant surveillance of the cells of the immune system. It is an active function and not just a situation of the immune cells ignoring certain things. The immune system is actually a tricky balance between a pro-inflammatory response and an anti-inflammatory one. If this homeostasis was not maintained, then the immune system would either become over-reactive to harmless antigens and lead to inflammatory disease or it would become so anti-inflammatory in nature that pathogens wouldn’t be properly kept under control.

Below, we present some detail regarding how the immune cells found in the intestines maintain tolerance.

Ingested Antigen (Food) Tolerance

To form tolerance against food, induced Tregs are mainly employed. Tregs come in two main types. There are ones that formed in the thymus during T cell development, called natural Tregs, and there is an induced version that is differentiated from naïve T cells located in lymphoid tissues, called induced Tregs. Induced Tregs are known to form in a wide variety of GALT and also spleen. Their induction depends on the type of DC that presents the antigen. One of the most well-studied types of DCs that induce Tregs is the CD103+ DC. This kind of DC is formed in an environment that is rich in retinoic acid. This in turn encourages the DC to produce the enzyme, RALDH2, which is necessary for the DC to make it’s own supply of retinoic acid. During its interactions with naïve T cells, the retinoic acid, in combination with another factor called TGFβ, encourages the T cell to differentiate into a Treg and have anti-inflammatory effector functions for the oral antigen. The job of the Tregs is to inhibit the effector functions of other immune cells, especially other pro-inflammatory T cells.

Commensal Tolerance

Besides regulating responses to the food, the immune system is also responsible for much of the communication with the intestinal flora. For the most part, the immune system works to be tolerant of its commensals. The cells of the epithelial layer are usually the first to interact with microbes that penetrate the mucus layers. When this happens, the epithelial layer cells use PRRs to detect and evaluate the invaders. Without regulatory mechanisms, this breach of security would lead to extreme pro-inflammatory responses; robust anti-microbial peptide and pro-inflammatory cytokine release. However, the immune system would rather tolerate commensal to prevent an all-out immune response.

Natural Tregs, are one of the most important anti-inflammatory mechanisms that allow for the tolerance of intestinal flora. They are formed in the thymus and are released in a state that already pre-disposes them to regulation as opposed to the induced Tregs, which are derived from naïve T cells. Many of these natural Treg have T cell receptors that recognise commensals and diffuse any responses generated by the stray microbes.

Secretory IgA produced by plasma cells is also important to maintaining commensal tolerance. Secretory IgA coats commensals and traps them in the mucus, preventing them from getting close to the epithelial layer. While the precise functions of sIgA are still unknown, it may be that they also mark the bacteria as harmless, which would allow the epithelial cells to send out anti-inflammatory signals, when they accidently get close by. Although in depth studies still need to be done on sIgA, it has the potential to be key in maintaining commensal tolerance.

Summary

The intestines contain immune cells that are important for maintaining the health of the digestive tract. The GALT and the LP are where the majority of the immune cells reside. During conditions of health, the GALT supports the development of anti-inflammatory adaptive immune responses towards harmless antigens originating from food and the intestinal microbiota. These anti-inflammatory responses are spearheaded by natural and induced Tregs along with sIgA. These responses effectively inhibit damaging pro-inflammatory responses that would, otherwise, be initiated. This delicate homeostasis allows us to live with our intestinal flora and not have an immune reaction to the food that we eat.

References

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