Tipping the balance: inhibitory checkpoints in intestinal homeostasis

Abstract

The small intestinal and colonic lamina propria are populated with forkhead box P3 (FOXP3) + CD4 + regulatory T cells (Tregs) and interleukin-10-producing T cells that orchestrate intestinal tolerance to harmless microbial and food antigens. Expression of coinhibitory receptors such as CTLA-4 and PD-1 serve as checkpoints to these cells controlling their T-cell receptor (TCR)-mediated and CD28-mediated activation and modulating the phenotype of neighboring antigen presenting cells. Recent discoveries on the diversity of co-inhibitory receptors and their selective cellular expression has shed new light on their tissue-dependent function. In this review, we provide an overview of the co-inhibitory pathways and checkpoints of Treg and effector T cells and their mechanisms of action in intestinal homeostasis. Better understanding of these inhibitory checkpoints is desired as their blockade harbors clinical potential for the treatment of cancer and their stimulation may offer new opportunities to treat chronic intestinal inflammation such as inflammatory bowel disease.

Mechanisms of activation of innate-like intraepithelial T lymphocytes

“…Protein level expression of LAG-3, 10 , 94 TIGIT, 35 and Gp49 112 on CD8αα T-IEL has been confirmed by flow cytometry, while CTLA-4 is only expressed on CD8αβ + αβ T-IEL. 10 Although the functions of these receptors on other adaptive CD4 + and CD8 + T cells, and on intestinal T cells is well described and has been reviewed recently, 122 to our knowledge, their role on T-IEL has never been studied.…”

Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

“…We previously postulated that high expression of these immune-inhibitory receptors in the gut may be an important regulatory mechanism to limit unnecessary CD4 T cell activation in response to the local enteric commensal microbial community [18]. Certainly, their critical role in controlling gut T cell immunity is highlighted by recent observations that cancer-based immunotherapies designed to block these molecules can sometimes lead to unintended immune-mediated gut inflammation [35,36]. A number of studies have linked age-associated systemic inflammation to gut epithelial barrier dysfunction, local inflammation and/or dysbiosis [3][4][5][6][7][8][9][10].…”

Fine tuning of the DNAM-1/TIGIT/ligand axis in mucosal T cells and its dysregulation in pediatric inflammatory bowel diseases (IBD)

“…Further, TIGIT identified exhausted/ hypofunctional CD8 + T cells in different pathological settings. 1,3,4,[16][17][18][21][22][23]44 We have explored the possible mechanisms at the basis of the distinct expression profile of DNAM-1 and TIGIT co-receptors on mucosal T cells, and the factors that may contribute to the perturbation of this pattern in IBD. The analysis of mucosa-specific homing receptors on DNAM-1 + and TIGIT + T cells only partially supports a role for differential recruitment to explain the selective enrichment of TIGIT + T cells in healthy gut mucosa.…”

“…TIGIT may inhibit T-cell functions through several mechanisms: competition with DNAM-1 for their shared ligands, disruption of DNAM-1 homodimerization, interference with activating intracellular signaling cascades, and indirectly by either inducing Treg responses or by stimulating DC to produce interleukin (IL)-10. 7,[16][17][18][19][20][21][22][23] This system, where two different receptors with opposite functions are engaged by the same ligands, potentially expressed on the same target cell, suggests an intriguing role of DNAM-1 and TIGIT in the fine-tuning of T-cell functions in distinct microenvironments, characterized by different ligand availability.…”