CXCR3^high CD8⁺ T cells with naïve phenotype and high capacity for IFN‐γ production are generated during homeostatic T‐cell proliferation

Abstract

Naïve phenotype (NP) T cells spontaneously initiate homeostatic proliferation (HP) as T-cell output is reduced because of physiologic thymic involution with age. However, the effects of sustained HP on overall immune function are poorly understood. We demonstrated that the NP CD8 T cell population in adult thymectomized mice showing accelerated HP has an increased capacity for TCR-mediated interferon-γ and tumor necrosis factor α production, which is attributed to an increase in CXCR3 cells in the NP CD8 T cell population. The CXCR3 NP CD8 T cells developed during persistent HP with a slow cell division rate, but rarely during robust antigen-driven proliferation with a fast cell division rate. In ontogeny, the proportions of CXCR3 cells in the NP CD8 T cell population showed a biphasic profile, which was high at the newborn and aged stages. Upon transfer, CXCR3 NP CD8 T cells, but not CXCR3 NP CD8 T cells, potently enhanced Th17-mediated inflammatory tissue reactions in vivo. Furthermore, CXCR3 NP CD8 T cells with similar features were also detected at variable levels in healthy human blood. These results suggest that CXCR3 NP CD8 T cells generated during physiological HP significantly impact overall immunity at the immunologically vulnerable neonatal and aged stages.

CXCR3 Identifies Human Naive CD8+ T Cells with Enhanced Effector Differentiation Potential

“…TRECs were modestly diluted in T N R3 + cells compared with T N R3 − cells, indicating a slightly higher rate of homeostatic turnover in vivo, akin to that observed previously for CD5 hi T N cells compared with CD5 lo T N cells in lymphopenic mice (23). Homeostatic proliferation may even drive the acquisition of CXCR3 (74). In this scenario, T N R3 + cells would arise as a natural consequence of enhanced tonic signaling via qualitatively distinct TCRs with a predilection for self-derived Ags.…”

Aging and CMV Infection Affect Pre-existing SARS-CoV-2-Reactive CD8+ T Cells in Unexposed Individuals

“…In addition to the proportional changes in NP and MP T cells, recent studies have revealed that T cell populations with highly differentiated phenotypes and/or cellular senescence characteristics accumulate with age; senescent T cells show an increased expression of DNA damage markers [e.g., phosphorylated histone H2AX (γH2AX)], shortened telomeres, and low telomerase activity ( Akbar et al, 2016 ). We previously reported that T-cell senescence was induced by prolonged homeostatic proliferation to compensate for the decrease in thymic T cell production in a mouse model ( Sato et al, 2017 ; Kato et al, 2018 ; Minato et al, 2020 ). CD57 expression defines replicative senescence in human T cells ( Brenchley et al, 2003 ), and patients thymectomized during early childhood show an early accumulation of CD57 + senescent T cells during their lifetime ( Sauce et al, 2009 ).…”

The Role of CXCR3 and Its Chemokine Ligands in Skin Disease and Cancer

“…CXCR3 (GPR9/CD183) is an interferon-inducible chemokine receptor expressed on various cell types, but preferentially monocytes, Th1 T cells, CD8 T cells, NKT cells, NK cells, dendritic cells, and some cancer cells ( 19 – 21 ). Homeostatic proliferation of T cells in immune depleted individuals can also lead to an enrichment of CXCR3 + T cells ( 22 ). The CXCR3 receptor reacts with three interferon-inducible chemokines: CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC/IP-9) in addition to CXCL4.…”