CXCR3high CD8+ T cells with naïve phenotype and high capacity for IFN-γ production are generated during homeostatic T-cell proliferation.

Abstract

Naïve phenotype (NP) Tcells 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+ Tcell 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+ Tcell population. The CXCR3+ NP CD8+ Tcells 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+ Tcell population showed a biphasic profile, which was high at the newborn and aged stages. Upon transfer, CXCR3+ NP CD8+ Tcells, but not CXCR3- NP CD8+ Tcells, potently enhanced Th17-mediated inflammatory tissue reactions in vivo. Furthermore, CXCR3high NP CD8+ Tcells with similar features were also detected at variable levels in healthy human blood. These results suggest that CXCR3+ NP CD8+ Tcells generated during physiological HP significantly impact overall immunity at the immunologically vulnerable neonatal and aged stages.