High levels of metabolites produced by Clostridia and their colonization in close proximity to the intestinal mucosa allows us to hypothesize that Clostridia exert a strong influence on the host immune system. Indeed, it has been showed that Clostridia can promote the development of αβ T cell receptor intraepithelial lymphocytes (IEL) and immunoglobulin A (IgA)-producing cells in the large intestine [
78]. IEL, IgA-producing cells within the lamina propria, and intestinal epithelial cells are key players in determining the nature of the immunological response to antigens or pathogens ingested. Germ free animals show a reduced number, low Thy-1 expression, and low cytolytic activity, of IEL [
79,
80]. Furthermore, IgA production is rare [
81] and macroscopic Peyer’s patches are small and poorly developed in comparison with those in conventionally-housed animals [
82]. Umesaki
et al. assessed that germ free mice inoculated with 46 strains of Clostridia singly isolated from conventional mice showed an increase in the ratio of CD4
- CD8
+ cells to that of CD4
+ CD8
- in αβIEL within the large intestine. Conversely, the number and phenotype of IEL were similar to those in conventionally-housed mice. The number of IgA-producing cells in the colons of mice treated with Clostridia was slightly increased compared to that in germ free mice [
78]. Thus, Clostridia appear to be involved in the promotion of immunological development [
78] in the large intestine, but not in the small intestine. The same study showed that in the small intestine, these changes were due to the presence of
segmented filamentous bacteria[
78], suggesting the occurrence of compartmentalization of the immunological responses to indigenous bacteria and of Clostridia in exerting their specific role in gut homeostasis. Moreover, commensal Clostridia are able to normalize cecal size when they are associated with germ free mice [
83]. How the immune system fundamentally senses Clostridia remains unclear. In this context, it has been suggested that the presence or gradient of SCFAs and secondary bile acids produced by Clostridia may be sensed by epithelial cells and in turn, may be associated with the initiation of immunological signaling [
78], due to the cross talk between epithelial and immune cells. For example, IL-7 secreted by epithelial cells can activate IL-7 receptor-bearing IEL on their progenitors [
84,
85]. Furthermore, IL-6 [
86] and transforming growth factor β [
87] produced by the epithelia during infection can stimulate the development of Peyer’s patches and IgA production [
88].
Clostridium spp. belonging to clusters XIV and IV have also been reported to be strong inducers of colonic T regulatory cell (Treg) accumulation [
89]. CD4
+Foxp3
+ Tregs are the most prominent regulatory cells in the body and are most abundant in the colonic lamina propria [
90,
91]. Here, their frequency among CD4
+ T cells is notably higher than in other organs [
89], suggesting that the intestinal microbiota may be involved in the accumulation of colonic Tregs. Several reports have determined that intestinal Foxp3
+ Tregs are markedly affected by the intestinal microbiota [
92]. A fraction of intestinal Tregs express T cell receptors that recognize antigens derived from the gut microbiota [
93]. It has been established that these colonic Tregs play critical roles in intestinal immune homeostasis, suppressing systemic and mucosal immune activation to control intestinal inflammation, and contributing to maintaining tolerance towards gut microbiota [
94,
95]. Atarashi
et al. showed that colonization of germ free mice with a defined mixture of 46
Clostridium strains belonging to clusters XIVa and IV induced the accumulation and differentiation of colonic Tregs [
89].
Clostridium spp. were also able to promote increased expression of IL-10 in Treg [
89], expression of matrix metalloproteinases (MMPs), as well as activation of TGF-β [
96] and indoleamine 2,3-dioxygenase (IDO) in colonic epithelial cells [
89]. Intestinal epithelial cells are crucial for the maintenance of innate and adaptive immune homeostasis in the gut. Moreover, even the colonization with altered Schaedler flora (ASF), which includes
Clostridium clostridioforme, leads to the accumulation of Tregs within the colon [
97]. Consistent with these findings,
F. prausnitzii, which belongs to
Clostridium cluster
IV, increases IL-10 production from peripheral blood mononuclear cells
in vitro[
98]. How Tregs induced by commensal Clostridia can contribute to immune homeostasis in the intestine is an important question to address. Foxp3
+ cells with TCRs specific for CBir1, a flagellin related to those of
Clostridium cluster
XIVa, induce IgA
+ B cells in the intestine in order to reduce the mucosal uptake of microbiota-derived antigens and prevent systemic T cell activation [
99]. Therefore,
Clostridium spp. can affect the number and function of colonic Tregs, inducing naive CD4
+ T cells to differentiate into antigen-specific colonic Tregs that are able to enforce immune tolerance towards commensal bacteria. It is interesting to note that even conventional T cells express TCRs specific for commensal antigens, and are potentially colitogenic if not completely suppressed by intestinal Tregs [
100]. Notably, elevated levels of
Clostridium clusters
XIVa and
IV in mice leads to resistance to allergy and intestinal inflammation in experimental models [
89]. Conversely, the microbiota of individuals with chronic inflammation show lower bacterial diversity and it has been determined that
Clostridium clusters
IV, particularly
F. prausnitzii, and
XIVa are significantly less abundant in IBD patients compared to healthy subjects [
14,
98,
101]. It is still unknown whether the decrease in Clostridia is a cause or a consequence of chronic inflammation in IBD patients and in autoimmunity, but we can speculate that they are necessary for immune homeostasis, contributing to the suppression of autoimmunity and deleterious inflammation in humans.