Disrupted regulatory T cell homeostasis in inflammatory bowel diseases

Abstract

In the gut, where billions of non-self-antigens from the food and the microbiota are present, the immune response must be tightly regulated to ensure both host protection against pathogenic microorganisms and the absence of immune-related pathologies. It has been well documented that regulatory T cells (Tregs) play a pivotal role in this context. Indeed, Tregs are able to prevent excessive inflammation, which can lead to the rupture of intestinal homeostasis observed in inflammatory bowel diseases (IBDs). Both the worldwide incidence and prevalence of such diseases have increased throughout the latter part of the 20(th) century. Therefore, it is crucial to understand how Tregs suppress the colitogenic immune cells to establish new treatments for patients suffering from IBDs. In this review, we will first summarize the results obtained in animal model studies that highlight the importance of Tregs in maintaining intestinal homeostasis and describe the specific suppressive mechanisms involved. Next, our current knowledge about Tregs contribution to human IBDs will be reviewed, as well as the current therapeutic perspective on using Tregs for clinical IBD treatment and the challenges that remain to be resolved to ensure both the safety and effectiveness of these therapies in targeting this critical immune-regulatory cell population.

Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies

“…Furthermore, autoimmune GI disease can be robustly induced (27-54% symptomatic with watery diarrhea) upon treatment with anti-CTLA4 biologics (126). These data again converge on the hypothesis that Tregs are critical in gut homeostasis (127). To this end, infiltrating T cells have been demonstrated on intestinal biopsy in CTLA4 haploinsufficiency (83), and lack of response to traditional therapeutics including TNF-α inhibitors has been demonstrated in LBRA deficiency (120).…”

Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor

“…In IBD, the ability of transferred Treg to control inflammatory lesions has been demonstrated in rodent models of IBD 8, 9, 10. In addition, the Treg frequency in the peripheral blood was significantly lower in patients with active IBD than in healthy control subjects, suggesting disrupted Treg homeostasis in IBD 11, 12. Thus, Tregs may play a role in suppression of IBD 13 …”

Subclinical Nasal and Lung Lymphocytosis in Ulcerative Colitis

“…Furthermore, the discoveries of genes related to T-helper-17 cell differentiation and function, and genes influencing innate immunity and microbial immune response, have brought major insights into disease pathogenesis, pointing to altered bacterial handling as a key factor in disease pathogenesis [11, 12]. A number of clinical observations and experiments in animal models have demonstrated a key role played by regulatory T cells, CD4+CD25+ (Tregs), in the pathogenesis of IBD and in the appearance of its systemic manifestations [13]. …”