Tissue-Resident Memory T Cells in Chronic Inflammation-Local Cells with Systemic Effects?

Abstract

Chronic inflammatory diseases such as rheumatoid arthritis (RA), Juvenile Idiopathic Arthritis (JIA), psoriasis, and inflammatory bowel disease (IBD) are characterized by systemic as well as local tissue inflammation, often with a relapsing-remitting course. Tissue-resident memory T cells (T_RM) enter non-lymphoid tissue (NLT) as part of the anamnestic immune response, especially in barrier tissues, and have been proposed to fuel chronic inflammation. T_RM display a distinct gene expression profile, including upregulation of CD69 and downregulation of CD62L, CCR7, and S1PR1. However, not all T_RM are consistent with this profile, and it is now more evident that the T_RM compartment comprises a heterogeneous population, with differences in their function and activation state. Interestingly, the paradigm of T_RM remaining resident in NLT has also been challenged. T cells with T_RM characteristics were identified in both lymph and circulation in murine and human studies, displaying similarities with circulating memory T cells. This suggests that re-activated T_RM are capable of retrograde migration from NLT via differential gene expression, mediating tissue egress and circulation. Circulating 'ex-T_RM' retain a propensity for return to NLT, especially to their tissue of origin. Additionally, memory T cells with T_RM characteristics have been identified in blood from patients with chronic inflammatory disease, leading to the hypothesis that T_RM egress from inflamed tissue as well. The presence of T_RM in both tissue and circulation has important implications for the development of novel therapies targeting chronic inflammation, and circulating 'ex-T_RM' may provide a vital diagnostic tool in the form of biomarkers. This review elaborates on the recent developments in the field of T_RM in the context of chronic inflammatory diseases.

Keywords: chronic inflammation; re(circulation); tissue–resident memory T cells.

Figure 1

Key cytokines and transcription factors for the development of tissue–resident memory T cells (T_RM). T_RM are derived from memory precursors effector cells that express low KLRG1 and high CD127. Analysis of development has shown that T_RM displayed plasticity intermediate between tissue central-memory (T_CM) and tissue effector-memory (T_EM), and are not as terminally differentiated as previously believed. The central cytokine that induces T_RM differentiation is transforming growth factor β (TGFβ). TGFβ induces downregulation of T-bet and Eomes, which is essential for T_RM formation. Blimp1, Hobit, and Runx3 play a role in T_RM differentiation as well. Upregulation of Hobit is observed in mice T_RM, but only in a subset of human T_RM.

Figure 2

Models of the recall immune response by memory T cells. The left panel shows the ‘inside-out’ model, where T_RM are local tissue mediators of the anamnestic immune response, proliferating inside their tissue upon reactivation. T_CM and T_EM constitute the systemic recall response in this model. T_CM are activated in deeper tissues i.e., draining lymph nodes at site of infection, proliferating and migrating towards affected tissue sites. The right panel shows the recently proposed ‘outside-in’ model. In this mode anamnestic immune response is generated at site of infection. T_RM are activated at barrier tissues and migrate inwards, to lymph and circulation, with the potential to differentiate into T_CM and T_EM (highlighted by the arrows in red). The blue arrows represent the T cell traffic under chronic inflammatory (permanently activated) states [18,21,22,65,66].

Figure 3

T cells resembling tissue–resident memory T cells (T_RM) from various tissues have been identified. Subsets of memory T cells with characteristics of T_RM were identified in the circulation of Juvenile Idiopathic Arthritis (JIA), RA, and AS (with inflammatory bowel disease (IBD)) patients. These cells displayed an activated, effector pathogenic phenotype, and were clonally related to their tissue counterparts. This suggests that these cells may be ex-T_RM, having egressed from the tissue of origin. Cells resembling synovial fluid (SF) Tregs were also identified in circulation.