The gastrointestinal tract contains a vast number and a diverse array of immune cells, which together form the largest immune system in the body. Inflammatory pathways in the gut mucosa are finely controlled by the stringent mechanisms under homeostatic conditions. In the gut mucosa of IBD, excessively activated innate immune cells present antigens and secrete inflammatory cytokines, resulting in the aberrant activation of adap-tive immune cells, which in turn leads to the further infiltration of inflammatory immune cells into inflamed sites and exacerbates tissue damage. Regardless of the genetic and environmental variances of the patient cohort, dysregulated immune responses may finally converge on the common T cell–mediated inflammatory cascades, which are the direct drivers of inflammatory bowel disease (IBD). Despite a plethora of studies emphasizing the involvement of T cells in the pathogenesis of IBD and extensive efforts to develop T cell–directed strategies, no disease-specific T cell subset that plays an essential role in the progression of IBD has been identified.
The classically proposed theory of T helper1 (Th1) and Th2 imbalance in IBD is based on the cytokine context. T cells are highly plastic, which may arise from a flexible genetic program in response to local environmental cues or heterogeneity of the cells. It is thus important to resolve how immune cell populations display pronounced diversity in the pathological settings of IBD and which of these cells contribute to pathogenesis. In contrast to circulating T cells, which patrol the entire body via lymphatic and blood flow, tissue-resident T cells (TRM) remain within nonlymphoid barrier tissues and serve as the frontline of host defense. The contribution of TRM to the pathogenesis of IBD has been controversial, with conflicting results often being obtained in human and animal studies. This controversy is due not only to differences in patients’ backgrounds but also to heterogeneity of TRM. In particular, the functional properties of CD4+ TRM in pathological settings have remained largely unknown, as opposed to CD8+ TRM, which have been extensively studied.
Interferon gamma (IFN-γ) is known to be involved in IBD pathogenesis. Indeed, IFN-γ has been shown to be increased in the lamina propria of CD patients and is required for inducing inflammation in colitis models. IFN-γ regulates intestinal epithelial homeostasis and drives IBD pathogenesis through vascular barrier disruptio. Despite this plethora of findings indicating that IFN-γ is profoundly involved in intestinal inflammation, its specific neu-tralizing antibody fontolizumab has had limited efficacy in clinical trials, suggesting that additional factors are required for disease development. Intriguingly, IFN-γ, in synergy with TNF-α, promotes the apoptosis of intestinal epithelia. This is note-worthy because a neutralizing antibody specific for TNF-α resulted in remarkable clinical improvement, in contrast to the poor clinical efficacy of many other anti-cytokine monoclonals. Furthermore, Th17 cells, which have recently received attention as the core of IBD pathogenesis, have considerably high plasticity.
Crohn disease (CRO) and ulcerative colitis (URC) display distinct patterns of immune networks, which are transcriptionally wired by the programs acting in opposing directions. In contrast to the accumulation of CD4+ TRM in CRO patients, TCF7++ T cells were increased in a proportion of URC patients. While some memory T cells are designed to circulate through the bloodstream and provide whole-body protection, others reside in specific organs and are specialized to fight the pathogens that target that part of the body. These TRM cells can provide life-long immunity at the target tissue, but can also contribute to autoimmune diseases if overactivated. In a new study published in the journal Immunity, scientists at University of California San Diego School of Medicine revealed a previously unappreciated complexity of TRM cell biology in the gut, which may inspire a new generation of precision therapeutics against infection, cancer and auto-immune diseases of the IBD subgroup.
TRM cells are the first responders, right at the front lines of infection. Most of our vaccines are designed to provide systemic immunity, but we may be able to get even better protection by instead focusing on boosting the tissue-specific cells that encounter the pathogen first. For example, a respiratory virus may be best fought by strengthening TRM cells in the nose and lungs, and a pathogenic gut microbe best treated by enhancing TRM cells in the intestines. Thus the goal is to develop therapeutics that could boost the formation and maintenance of these cells, or in the case of autoimmune disease, remove themby disrupting these same pathways. The issue is, scientists still have a lot to learn about what helps TRM cells form and survive. To explore this, the researchers performed a series of experiments to characterize TRM cells in mice from four different compartments of the gut: two organs (the small intestine and the colon) and two different tissue layers in each (the intraepithelial and lamina propria layers).
The experiments revealed that TRM cells in each tissue type exhibited distinct patterns of cytokine and granzyme expression, along with substantial transcriptional, epigenetic and functional heterogeneity. In other words, the same type of immune cells in each part of the gut appeared to be very different in their molecular makeup, function and the chemical signals they depend on. Reinforcing this further, each population of cells also showed differential dependence on Eomesodermin (Eomes), a transcriptional factor known to affect TRM cell development. Eomes is a member of the T-box family of transcription factors, along with T-bet, and has been found to impact CD4 T cell responses in a variety of different settings. Subsequent studies employing Eomes overexpression and more recently developed conditional Eomes knockout mouse models have revealed important roles for Eomes in CD8 T cells, natural killer (NK) cells, and innate lymphoid cells. Like most transcription factors impacting CD4 T cell responses, Eomes is regulated by multiple mechanisms.
Antigen stimulation via the T cell receptor (TCR) during T cell activation is a critical regulator of Eomes induction, as it is nearly undetectable in naïve CD4 T cells. Interleukin-2 (IL-2), the critical autocrine T cell growth factor induced by TCR stimulation, and involved in inflammation for Crohn disease and ulcerative colitis, does not seem to directly regulate Eomes. Interestingly, though, CD4 T cells deficient in STAT5, an important mediator of IL-2 signaling, are marked by increased Eomes expression. On the contrary, Eomes does not directly impact the regulatory capacity of regulatory lymphocytes (Tregs), that are critical for preventing aberrant T cell responses and potentially damaging inflammation. Eomes was canonically thought to repress TRM cells based on previous data collected from the skin, liver and kidney, but the new experiments revealed the opposite was true in the small intestine. The relative expression level of T-bet by CD4 T cells responding to infection may play a particularly important role in establishing tissue-resident memory populations, at least in the lung.
Correlations between increased T-bet expression and decreased respiratory CD4 TRM formation following viral infection have also been seen in clinical studies. One of the mechanisms by which Eomes may promote CD4 TRM is by regulating expression of the transcription factor Hobit, a control mechanism identified as necessary for supporting CD8 TRM formation during cytomegalovirus infection. Hobit has also been shown to direct intestinal CD4 TRM formation. There, Eomes proved to be surprisingly important in the survival of TRM cells. However, this was not the case in the colon, highlighting the high context-specificity even within the gut. Future research will continue to define the rules of TRM cell formation and maintenance in other tissues and explore what drives their specificity. For example, the authors suggest that differences in the microbiota of the small intestine and the colon may contribute to the unique needs of their TRM cells, so manipulating the microbiota may be another approach to regulating immune cells in the gut. The problem is to find how.
At the same time, a more comprehensive understanding of the full scope of signals that modulate Eomes expression and that are impacted by its expression, represents an important goal that could provide novel strategies to optimize immunity and to fight autoimmune diseases like IBD itself and others.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Dott. Gianfrancesco Cormaci
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