Immunological pathogenesis of inflammatory bowel disease: focus on tissue resident memory T cells

Abstract

Tissue-resident memory T (T_RM) cells are a type of tissue-restricted memory T cells with terminal differentiation and a memory function. They exist in mucosal tissues for a long period. In the absence of disease, T_RM cells promote essential inflammation, which reinforces the intestinal barrier and prevents bacterial translocation. However, in inflammatory or autoimmune environments, T_RM cells are hyperactivated. This heightened activity causes the host to release excessive pro-inflammatory cytokines, resulting in local immune imbalances and damage to the barrier, ultimately leading to tissue lesions. Numbers of studies have shown that T_RM cells play a crucial role in the development and progression of inflammatory bowel disease (IBD), suggesting that targeted regulation of T_RM cells homeostasis may be an important strategy for treating IBD. Here, we compiled the existing understanding of the role of T_RM cells in IBD, with particular emphasis on the associated mechanisms and approaches for targeting T_RM cells in IBD treatment. This review will serve as a foundation for a better understanding of IBD development and enhancing the effectiveness of clinical treatments for IBD.

Keywords: immune balance; inflammatory bowel disease; mechanisms; strategies; tissue-resident memory T cells.

Figure 1

The role of T_RM cells in inflammatory bowel disease. When the intestinal epithelial layer is compromised, antigens from the intestinal lumen, including microbiota and pathogens, can penetrate the barrier and access the intestinal lamina propria. Under stress, T_RM cells upregulate LepR signaling and downstream HIF-1α expression to rapidly enhance energy production in response to antigen infection. This leads to a significant increase in Glut expression and glycolytic activity. With additional stimulation from TGF-β, pre-existing T_RM cells undergo local proliferation and play a key role in effective recall responses. Some of these T_RM cells may re-enter the circulation, showing a preference for migrating back and the potential to re-differentiate into T_RM cells. A fraction of T_RM cells undergo rapid proliferation and exhibit a greater propensity to differentiate into pro-inflammatory subsets, accompanied by the degradation of certain regulatory subsets. This change leads to an increased expression of inflammatory cytokines, chemokines, and cytotoxic granules. T_RM cells secrete proinflammatory cytokines, including IFN-γ, IL-2, and TNF-α, which activate natural killer (NK) cells and dendritic cells (DC). This process enhances neutrophil infiltration and recruits additional immune cells by increasing the expression of VCAM-1 on endothelial cells. Ultimately resulting in inflammatory infiltration and causing the development of IBD. At the same time, CD4⁺T_RM cells in the lamina propria are closely located to the intestinal epithelium, directly damage to intestinal epithelium. T_RM, tissue-resident memory T cells; LepR, leptin receptor; HIF-1α, hypoxia-inducible factor 1 alpha; LDHA, lactate dehydrogenase; OXPHOS, oxidative phosphorylation; IFN, interferon; IL, Interleukin; DC, dendritic cells; TNF, tumor necrosis factor; TGF, transforming growth factor; NK, natural killer; VCAM, vascular cell adhesion molecule; ICOS, Inducible synergistic co-stimulation molecules; CTLA-4, Cytotoxic T-lymphocyte associated protein 4; Foxp3, Forkhead box protein P3.

Figure 2

Targeted therapeutic strategies employing T_RM cells in the treatment of IBD. CD127⁺KLRG^-T_EM cells can be activated into T_RM cells in reaction to TNF-α and TGF-β. The inhibition of TNF-α activity (using Infliximab, Golimumab, and Adalimumab) effectively suppresses the activation of T_RM cells. After activation, T_RM cells migrate from the circulation to the intestinal mucosa by upregulating the expression of αEβ7, α4β7, and CCR9 while downregulating S1PR1 expression. Therefore, downregulating the expression of CCR9 (CCX282-B), αEβ7 (Etrolizumab), and α4β7 (Vedolizumab), inhibiting the binding of MAdCAM-1 to α4β7 (PF-00547659), and upregulating S1PR1 expression (Etrasimod, Ozanimod) can reduce T_RM cell homing. The upregulation of PD-1 and the reduction of IL-23 (Ustekinumab) will promote the apoptosis of T_RM cells. Finally, Rapamycin boosts the differentiation, proliferation, and distribution of Treg cells by inhibiting mTOR.