Review
Balancing acts: the role of TGF-β in the mucosal immune system

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The gastrointestinal mucosal immune system faces unique challenges in dealing not only with fed antigens but also both commensal and pathogenic bacteria. It is tasked with digesting, transporting and using nutritional antigens while protecting the host from pathogenic organisms. As such, mechanisms that mediate effective immunity and immune tolerance are active within the gut environment. To accomplish this, the mucosal immune system has evolved sophisticated mechanisms that safeguard the integrity of the mucosal barrier. Transforming growth factor-β (TGF-β) emerges as a key mediator, balancing the tolerogenic and immunogenic forces at play in the gut. In this review, we discuss the role of TGF-β in the generation and functioning of gut lymphocyte populations. We highlight recent findings, summarize controversies, outline remaining questions and provide our personal perspectives.

Section snippets

Transforming growth factor-β (TGF-β) and gut immunity

The gut simultaneously encounters both harmless and harmful antigens on a constant basis. Thus, the mucosal immune system tackles challenges not faced at other sites in the body. Differentiated T cell populations have been identified within the healthy gut, and these, coupled with a degree of tonic inflammatory signaling, play a vital role in promoting barrier function, protecting from invading pathogenic organisms, as well as preventing unwanted autoimmunity and overt inflammation. In the

TGF-β and regulatory T cell generation

Regulatory T cells (Tregs) (Box 2), are vital mediators of intestinal homeostasis; in their absence, gut pathology results. Indeed, the gut is a preferential site for the induction of Foxp3 in TCRαβ+CD4+ T cells (CD4+ T cells) (Table 1) 6, 7. It has been known for some time that induction of tolerance via the oral route leads to the generation of T cell populations with suppressive capacities [8], and this has been utilized in many animal models of autoimmune disease to alleviate symptoms.

Th17 differentiation

The pluripotency of TGF-β allows it to support the generation of a number of cell populations important in maintaining gut integrity (Figure 1). In addition to induction of Tregs, TGF-β promotes the differentiation of naïve T cells to the Th17 phenotype [22]. TGF-β achieves this indirectly by suppressing naive T cell differentiation into either Th1 or Th2 cells. Importantly however, TGF-β, in the presence of inflammatory cytokines such as IL-6, directly promotes differentiation of Th17 cells.

IgA production and the Treg–IgA axis

An important mechanism at play in the mucosa to promote immunity without causing inflammation is the production of IgA. Although many cytokine signals have been shown to be involved in the generation of IgA, the major cytokine signal is TGF-β-mediated [38]. IgA binds polymeric Ig receptors (pIgR) on the basolateral surface of intestinal epithelial cells and is then translocated across the epithelial cells to the gut lumen. IgA mediates protection at the mucosal barrier by two mechanisms: high

TGF-β retains lymphocytes in the gut

Following activation in lymph nodes, T cells traffic to tissues associated with the lymph node in which they were primed. For the gut, this means that cells activated in the GALT upregulate the gut homing molecules α4β7 and CCR9 and these direct gut trophism. Imprinting of α4β7 and CCR9 on both T and B cells is achieved by GALT APC that induce expression of homing molecules in an RA-dependent manner 44, 48. Again, we see that a specific subset of DC are associated with this function; CD103+ DC

TGF-β-dependent generation of TCRαβ+ CD8αα+ intraepithelial lymphocytes

Nestled between epithelial cells of the gut wall are intestinal intraepithelial lymphocytes (IEL). Owing to their location, IEL contribute to barrier function and the integrity of epithelial cells. As well as producing cytokines, total IEL have been shown to express junctional molecules important in preserving the epithelial barrier during infection [52]. IEL also form the first line of defense against invading pathogens, and it is suggested that this function accounts for the ‘activated but

Concluding remarks

In this review, we have discussed the most profound effects of TGF-β on lymphocytes in the dynamic immune environment of the gut. What is yet to be considered is how the TGF-β-mediated balance of Tregs and Th17 cells, Tregs and IgA production, lymphocyte gut trophism and IEL generation affect the systemic immune system. It is well established that the mucosal immune system of the gut can affect systemic immune functioning (for example, in oral tolerance), therefore it is possible that TGF-β

Acknowledgments

The authors would like to apologize for omitting the citation of many important primary articles due to length limitations. We would also like to thank Dr J.R. Grainger for critical reading of the manuscript. This research is supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research at the National Institutes of Health.

Glossary

CD8αα
homodimer of transmembrane glycoproteins expressed on the surface of some T cells (mainly IEL populations). CD8αα homodimers do not appear to act like the more typical T cell coreceptors, CD4 or CD8αβ, which promote T cell activity.
Colitis
inflammation of the colon.
Colitogenic T cell
colitis-causing populations of T cells.
Commensal bacteria
bacteria that colonize the gastrointestinal tract but cause no harm and instead confer advantages to the host.
Germ free mice
mice that are completely free

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