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

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.