CXCR5+CD8+ T Cells: A Review of Their Antibody Regulatory Functions and Clinical Correlations

Abstract

CD8+ T cells have conventionally been studied in relationship to pathogen or tumor clearance. Recent reports have identified novel functions of CXCR5+CD8+ T cells that can home to lymphoid follicles, a key site of Ab production. In this review, we provide an in-depth analysis of conflicting reports regarding the impact of CXCR5+CD8+ T cells on Ab production and examine the data supporting a role for Ab enhancement (B cell helper) and Ab downregulation (Ab-suppressor) by CXCR5+CD8+ T cell subsets. CXCR5+CD8+ T cell molecular phenotypes are associated with CD8-mediated effector functions, including distinct subsets that regulate Ab responses. Coinhibitory molecule PD-1, among others, distinguishes CXCR5+CD8+ T cell subsets. We also provide, to our knowledge, the first in-depth review of human CXCR5+CD8+ T cells in the context of clinical outcomes and discuss the potential utility of monitoring the quantity of peripheral blood or tissue infiltrating CXCR5+CD8+ T cells as a prognostic tool in multiple disease states.

Antibody-suppressor CXCR5+CD8+ T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice

“…This CD8 + T cell subset has been reported to impact biologic outcomes (infection, autoimmunity, malignancy) in various animal models of disease and in humans (reviewed in 46–48 ). Subsets of CXCR5 + CD8 + T cells have been reported to enhance antibody production, 49–58 while others like the antibody‐suppressor CXCR5 + CD8 + T cells in our studies and Qa1‐restricted CXCR5 + CD8 + T cells reported by others inhibit alloantibody 59 and auto‐antibody 60,61 production (reviewed in 62 ). Phenotypic, functional and mechanistic features of the antibody‐suppressor CXCR5 + CD8 + T cells in our studies that distinguish them from other subsets reported in the literature include the absence of PD‐1 expression 23,62 , antigen specific cytotoxic effector function targeting antibody‐producing B cells, 22,23 and regulatory functions that are not associated with FoxP3, IL‐10, ICOS/ICOSL, and CD103 62 …”

“…Subsets of CXCR5 + CD8 + T cells have been reported to enhance antibody production, [49][50][51][52][53][54][55][56][57][58] while others like the antibody-suppressor CXCR5 + CD8 + T cells in our studies and Qa1-restricted CXCR5 + CD8 + T cells reported by others inhibit alloantibody 59 and auto-antibody 60,61 production (reviewed in 62 ). Phenotypic, functional and mechanistic features of the antibody-suppressor CXCR5 + CD8 + T cells in our studies that distinguish them from other subsets reported in the literature include the absence of PD-1 expression 23,62 , antigen specific cytotoxic effector function targeting antibody-producing B cells, 22,23 and regulatory functions that are not associated with FoxP3, IL-10, ICOS/ ICOSL, and CD103. 62 Our prior work indicates that alloprimed CD8 + T cell-mediated suppression of alloantibody production occurs, in part, by the killing of alloprimed self-IgG1 + B cells (MHC I-restricted alloantigen presentation), which is detected both in vitro and in vivo.…”

“…Phenotypic, functional and mechanistic features of the antibody-suppressor CXCR5 + CD8 + T cells in our studies that distinguish them from other subsets reported in the literature include the absence of PD-1 expression 23,62 , antigen specific cytotoxic effector function targeting antibody-producing B cells, 22,23 and regulatory functions that are not associated with FoxP3, IL-10, ICOS/ ICOSL, and CD103. 62 Our prior work indicates that alloprimed CD8 + T cell-mediated suppression of alloantibody production occurs, in part, by the killing of alloprimed self-IgG1 + B cells (MHC I-restricted alloantigen presentation), which is detected both in vitro and in vivo. 22 In the current study, we found that compared to low alloantibody producing WT KTx mice, the high alloantibody producing CCR5 KO KTx mice have a relative deficit in quantity of CXCR5 + CD8 + T cells (and activated CXCR5 + CD44 + IFNγ + CD8 + T cells) in response to alloantigen stimulus (~5-fold reduction on day 7 posttransplant) that is accompanied by impaired alloprimed IgG + B cell directed cytotoxic effector function and enhanced proportion of GC B cells and plasma cells.…”

T‐cell activation–induced marker assays in health and disease

“…29 Of note, CXCR5expressing CD8 + T cells important for the control of autoantibody generation in the germinal center and for shaping the antibody response to viral infections. [62][63][64] It is important to note that while studies have shown chemokine receptors to be a useful alternative to cytokine detection, proper validation should be carried out to verify findings. This is especially important in disease cohorts, where alterations to chemokine receptor expression may occur in vivo.…”

“…In addition, it is possible to identify circulating Tfh (cTfh) based on CXCR5 and PD‐1 expression 29 . Of note, CXCR5‐expressing CD8 + T cells important for the control of autoantibody generation in the germinal center and for shaping the antibody response to viral infections 62‐64 …”