The role of senescent T cells in immunopathology

Abstract

The development of senescence in tissues of different organs and in the immune system are usually investigated independently of each other although during ageing, senescence in both cellular systems develop concurrently. Senescent T cells are highly inflammatory and secrete cytotoxic mediators and express natural killer cells receptors (NKR) that bypass their antigen specificity. Instead they recognize stress ligands that are induced by inflammation or infection of different cell types in tissues. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non-lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID-19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation.

Keywords: T cell; aging; senescence.

Figure 1

Leishmania infection results in infiltration of T_sen that aberrantly kill stressed and senescent stromal cells contributing to excessive damage. Leishmania infection of macrophages induces inflammatory cytokine production driving expression of MICA/B and other stress ligand on resident skin cells such as fibroblasts. Concurrently, these cytokines activate the endothelium which upregulates adhesion markers like E‐selection. This binds to CLA expressing senescent T cells enabling their infiltration into the skin. Here, these senescent T cells, expressing a host of NKRs including NKG2D interact with resident skin cells. The interaction between NKG2D⁺ T_sen and MICA/B⁺ fibroblasts results in killing of the latter and contributing to off‐target tissue pathology.