Our immune system must respond quickly to pathogenic factors, but also need to tolerate our own cells. This balanced behavior is unstable in the intestine, which is home to many harmless microorganisms, called the microbiome.
These microorganisms should not cause the immune system to respond, but if the immune system fails to tolerate them, this may lead to inflammation and the development of inflammatory bowel disease .
Recently, three studies published in the journal Nature elucidate the key processes required to inhibit the immune response to the microbiome.
regulatory T cells play a crucial role in ensuring that the microbiota is ignored. The regulatory T cell subpopulation expresses the protein CD4 and the transcription factor protein FOXP3.
is called immune cell , an
, that is called regulatory T (Treg) cells, plays a crucial role in ensuring that the microbiota is ignored. This inhibitory T cell subpopulation expresses the protein CD4 and the transcription factor protein FOXP3.
formation of immune cells that protect the gut microorganisms
Treg cells can inhibit self-nociceptive immune responses, thereby achieving what we call immune tolerance in a variety of ways, such as isolation factors that interact with proinflammatory cells or promote immune responses.
Treg cells are called thymus Treg cells and are produced by developing T cells in thymus . They are formed when cells called thymus medullae epithelial cells present fragments (autoantigens) that are normally present in the body to developing T cells (also known as initial T cells).
The presentation of the self- antigen on the cell surface depends on the expression of a protein called AIRE. Treg cells are produced in the peripheral parts of the body outside the thymus, such as the intestine, and are called peripheral Treg (pTreg) cells. When pTreg cells form, they express FOXP3 signaling mediated by the TGF-β protein.
Intestinal pTreg cells expressing the transcription factor protein RORγt appear early in life and play a central role in promoting tolerance to the microbiota when microorganisms colonize the intestine after birth. The generation of pTreg cells in the intestine can be mediated by a subpopulation 8 of immune cells called dendritic cells , which express the protein CD103 and present antigens on their cell surface using the main histocompatibility complex (MHCII) molecule of type 2. These cells can be described as traditional dendritic cells.
However, some reports highlight the ability of other antigen-presenting cells expressing MHCII and RORγt to mediate processes leading to peripheral tolerance, but their specific role in mediating tolerance is not fully understood.
These antigen presenting cells are described as subpopulations of extrathymic cells expressing AIRE (called eTACs or Janus cells) and are also described as group 3 inherent lymphoid cells (ILC3), but the exact relationship between these different cell types is not yet known.
These cells have been shown to play a role in immune tolerance because intestinal inflammation occurs in mice if RORγt-expressing cells from non-T cells are modified to lack MHCII.
This suggests that RORγt-expressing cells need to present antigens to T cells for immune tolerance, thus making the gut microbiota ignored. The identity of antigen presenting cells that promote differentiation of RORγt-expressing pTreg cells to help immune tolerate antigen presenting cells remains unclear, and this information may provide strategies for the prevention and treatment of inflammatory bowel disease.
These three new studies reveal that antigen presenting cell promotes the generation of pTreg cells expressing RORγt in the intestine. All three rule out the role of traditional dendritic cells inducing pTreg cells, which is consistent with previous work.
All three studies investigated whether antigen presenting cells expressing RORγt may be the culprit. In fact, knocking out MHCII in RORγt-expressing cells resulted in a decrease in intestinal Treg cells expressing RORγt.
In addition, while Treg cells are reduced, a T cell (effector helper T cell 17 [TH17] cells) in the intestine mediating an inflammatory immune response is increased, suggesting that different antigen presenting cells are responsible for induction and maintenance of intestinal pTreg and effector TH17 cells.
In addition, antigen presenting cells expressing RORγt-expressing MHCII itself is sufficient to produce pTreg cells expressing intestinal RORγt.
researchers evaluated the expression of gene , and evaluated the difficulty of different gene expression in cells taken from certain immune sites in the intestinal tract (called lymph node ) and found different subpopulations of of cell lines expressing RORγt. In addition to ILC3 cells, these subpopulations include previously reported Janus cells, as well as four subpopulations of Thetis cells described by Akagbosu et al. (called TC I to TC IV).
However, the relationship between these Thetis cells and previously described Janus cells requires further investigation. These studies highlight the complexity of RORγt-expressing antigen presenting cells and provide insights on gene expression tags, developmental requirements, and similarities and differences in markers that distinguish them. The purpose of the
study was to determine the mechanisms of forming these RORγt-expressed pTreg cells in the intestine. A key factor that promotes Treg cells is TGF-β, which needs to be activated after cell secretion, for example by a protein called integrin αvβ8.
Current research reports that when RORγt-expressing cells lack αv subunits (as shown in Lyu et al. and Kedmi et al.) or β8 subunits (as reported by Akagbosu et al.), or as described by Kedmi and colleagues, the number of pTreg cells expressing RORγt in the intestines decreased when mice received antibody treatment to target β8.
However, all three studies showed that ILC3 cells appear to express little or no β8, suggesting that β8 expression on non-ILC3 ror γt-expressing cell populations may play an important role in promoting ror γt-expressing Treg cells through integrin αvβ8. Akagbosu and colleagues reported that the most likely cell type that causes this phenomenon appears to be TC IV, which expresses higher levels of integrin β8 than other RORγt-expressing cell populations analyzed. Interestingly, data reported by Lyu and colleagues show that ILC3 cells promote the survival of RORγt-expressed Treg cells by expressing a different integrin called integrin αvβ3, which was previously not associated with induction of pTreg cells.
integrin αvβ3 can not only bind to TGF-β and activate, but also bind to several other proteins . Therefore, further studies are needed to study the role of Treg cells that promote RORγt expression through integrin αvβ8 and ILC3 cells in Treg cells that promote RORγt expression through integrin αvβ3 in vivo. A key question is which RORγt-expressing antigen presenting cell population (if any) has a necessary (non-redundant) effect in promoting the generation of pTreg cells expressing RORγt and FOXP3 and tolerating microbiota.
In two studies, different methods of eliminating MHCII expression in ILC3 cells yielded opposite results: the work of Lyu and colleagues showed that this defect led to a decrease in intestinal RORγt-expressing pTreg cells, whereas Akagbosu and colleagues found no effect.
These results leave a question of whether ILC3 cells play a key role in pTreg cells that promote RORγt expression. There is currently a lack of a genetic system that specifically removes Setis cells.
Analysis of mice lacking MHCII in AIRE-expressing cells or mice lacking AIRE-expressing cells showed that intestinal RORγt-expressing pTreg cells did not decrease compared with control animals.
However, these results may not be completely conclusive about the role of Thetis cells and AIRE, as in mice, the currently available genetic tools appear to have removed AIRE in only a small percentage of Thetis cells.
In addition, AIRE may be optional for the production of microbial specific Treg cells. Alternatively, as other studies have suggested, AIRE peripheral expression of Thetis cells or dendritic cells may play a role in peripheral tolerance to other antigens not associated with the microbiota, or by promoting functions independent of induction of pTreg cells.
These cell interactions that play a key role in the regulation of microbiota tolerance in mice may be evolutionarily conserved in humans.A population of dendritic cells expressing AIRE in human tonsils has been described previously.
Interestingly, Akagbosu and colleagues found a gene expression tag similar to TCⅲ and TCⅳ in a group of cells previously defined as dendritic cells in human fetal samples by analyzing single-cell data from previously published in fetal, child and adult intestinal drainage lymph node samples. Whether
ILC3, dendritic cells or thetis cell-like cells may play an antigen presentation role in promoting the formation of human pTreg cells still needs to be evaluated.
Immunologists are just beginning to understand how the host and its microbiome learn to live together. Answering the remaining questions may create new opportunities for promoting gut health and preventing the occurrence of immune-mediated diseases.
