IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Abstract

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)-responsive CD8 Tcell subset that was enriched in perforin, granzyme B, and interferon-␥ (IFN␥), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1-specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation. IntroductionA central feature of the adaptive immune response is the generation of antigen-specific effector and memory T cells. Naive T cells are induced to proliferate (clonal expansion) and differentiate upon encounter with cognate antigen presented by dendritic cells in secondary lymphoid structures. 1,2 Activation and subsequent differentiation lead to the formation of several CD8 T-cell memory subsets with different functional and migratory properties, classified as central memory, effector memory, and terminally differentiated effector memory cell subsets. 3,4 Terminally differentiated effector memory CD8 T cells express high levels of perforin, granzyme A and B, and Fas ligand; are highly cytotoxic; and home to sites of infection and inflammation. Effector memory CD8 T cells are thought to allow for a recall response in the tissue, as these cells survey nonlymphoid organs in search of cognate antigen and, while able to produce interferon-␥ (IFN␥) upon antigen recognition, are only moderately cytotoxic. In contrast, central memory cells recirculate between the blood and the lymphoid compartment and are thought to provide a pool of antigen-experienced cells with a high proliferative capacity but a lower activation threshold than naive cells, thus allowing for a more rapid generation of effector cells during a recall response. 3,5,6 Distinct migratory properties are a determining factor in T-cell subset function. Homing characteristics are thought to be controlled by the expression pattern of adhesion molecules and chemokine receptors acquired...

IL‐15‐induced human DC efficiently prime melanoma‐specific naive CD8+ T cells to differentiate into CTL

“…Indeed, recent studies have identified a subset of human CD8 + T cells that express CXCR1, respond to IL-8 and have cytotoxic function [22,23]. Memory CD8 + T cells do not express this receptor [22,23].…”

Properties of murine CD8+CD27- T cells

“…In uninfected mice the mean percentage of CD27 -cells within the lung CD8 + T-cell population was 11% and upon influenza infection this increased to 20% at day 9 and 29% at day 20 after infection ( Table 1). The increase in the lung at day 9 was possibly due to nonspecific migration of CD8 + CD27 -memory T cells in response to inflammatory mediators produced in inflamed lung [38][39][40] because at this time point nearly Liver 208 Table 2. In a CD27 x CD62L dot plot three subpopulations were identified: R1, CD62L + CD27 + ; R2, CD62L -CD27 + ; R3, CD62L -CD27 -.…”

Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists

“…IL-8 has been shown to recruit and activate neutrophil granulocytes [24], and stimulate IL-2-activated natural killer cells [25] and lymphokine-activated killer cells [26]. Recently, a subset of CD8 + T lymphocytes has been described, which is poised for immediate cytotoxicity and early recruitment by IL-8 into sites of innate immune activation [27,28]. Induction of IL-8 by muropeptides, therefore, may define a bacterial-specific response to enhance clearance from the infected host.…”