CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

Abstract

Naive and central memory CD8 T cells use CCR7 to recirculate through T cell zones of secondary lymphoid organs where they can encounter antigen. Here we describe a subset of human CD8 T cells expressing CXCR5 which enables homing in response to CXCL13 produced within B cell follicles. CXCR5 + CD8 T cells were found in tonsil B cell follicles, and isolated cells migrated towards CXCL13 in vitro. They expressed CD27, CD28, CD45RO, CD69, and were CD7 low , and produced IFN-c and granzyme A but lacked perforin, a functional profile suggesting that these cells are early effector memory cells in the context of contemporary T cell differentiation models. Receptors important in the interaction with B cells, including CD70, OX40 and ICOS, were induced upon activation, and CXCR5 + CD8 T cells could to some extent support survival and IgG production in tonsil B cells. Furthermore, CXCR5 + CD8 T cells expressed CCR5 but no CCR7, suggesting a migration pattern distinct from that of follicular CD4 T cells. The finding that a subset of early effector memory CD8 T cells use CXCR5 to locate to B cell follicles indicates that MHC class I-restricted CD8 T cells are part of the follicular T cell population. IntroductionCD8 T cells are lymphocytes of the adaptive immune system which recognize viral and bacterial peptides presented by MHC class I molecules and are indispensable in the control of many intracellular infections [1]. When appropriately stimulated by antigen presented by dendritic cells (DC) in secondary lymphoid tissues, they proliferate vigorously, become effector cells, and upon resolution of infection a small population of antigen-specific CD8 T cells are maintained as long-lived memory cells [2][3][4]. A primary effector mechanism of CD8 T cells is the killing of infected cells via the targeted release of the lytic effector molecules perforin and granzymes, and via expression of death receptors. However, there is significant functional heterogeneity in CD8 T cells and they are also efficient in producing anti-viral and pro-inflammatory cytokines [5][6][7][8]. The effector mechanisms used may depend on the pathogen and on the type of cell or tissue that is infected [8].CD8 T cell responses involve the differentiation of naive T cells into distinct types of effector and memory cells [2, 3,9]. One approach to analyse a T cell response is to examine the expression of receptors that mediate homing of T cells, such as CD62L, which binds to glycosylation-dependent cell adhesion molecule 1 on [4,20,21]. CXCR5 is a chemokine receptor which is expressed on all B cells and on specialized subsets of DC and T cells [22]. It has only one known ligand, the chemokine CXCL13, mainly produced by stromal cells and follicular DC within B cell follicles [23][24][25]. CXCR5 + CD4 T cells, known as follicular homing T helper cells, are found in B cell follicles and contribute to the generation of effective humoral immune responses by supporting antibody production and isotype class switching [26,27]. However, some of the processes and mec...

IL‐21 enhances the potential of human γδ T cells to provide B‐cell help

“…While the crucial role of T FH cells in providing B-cell help is undisputed, other T-cell subsets including CD8 1 T cells, NKT cells and gd T cells contribute to the outcome of humoral immune responses [8][9][10]. gd T cells support antibody production in immunised and infected mice [11][12][13] 110 [17,18], where they are scattered throughout the T zone and clustered within GCs [8].…”

“…1 T cells, NKT cells and gd T cells contribute to the outcome of humoral immune responses [8][9][10]. gd T cells support antibody production in immunised and infected mice [11][12][13].…”

“…Human T FH cells are defined by the expression of characteristic markers [3][4][5][6][7]: the transcriptional repressor Bcl-6 that directs T FH lineage commitment; the chemokine receptor CXCR5 that enables T FH cells to migrate into the B-cell follicles; the CXCR5 ligand CXCL13 that attracts further CXCR5 1 cells such as naïve B cells and early activated CD4 1 T cells; the co-stimulatory molecules, inducible co-stimulator (ICOS) and programmed cell death 1 (PD-1), which interact with their corresponding ligands on B cells; and the cytokine IL-21 that steers B-cell differentiation and antibody production. Murine T FH cells express the same panel of markers with the exception of CXCL13.While the crucial role of T FH cells in providing B-cell help is undisputed, other T-cell subsets including CD8 1 T cells, NKT cells and gd T cells contribute to the outcome of humoral immune responses [8][9][10]. gd T cells support antibody production in immunised and infected mice [11][12][13] 110 [17,18], where they are scattered throughout the T zone and clustered within GCs [8].…”

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions

“…Also, CD8 T cells are involved in downregulation of B cell responses in chronic LCMV infection, as CD8-deficient mice, or mice in which CD8 T cells have been depleted with Abs display induction of neutralizing Ab production (9,13). Under homeostatic conditions, B cell follicles contain very low numbers of CD8 T cells, and the function of these CD8 T cells is unclear (14). In contrast, during chronic infection, such as in HIV-1 infected patients, CD8 T cells appear to accumulate within the B cell follicles (15).…”

T Cell Response in Acute Motor Axonal Neuropathy

“…B cells producing anti ganglioside antibodies in GBS have been shown to be T celldependent, and it has been suggested that T cells obtained from the blood of GBS patients provide help for anti-glycolipid antibody production (36). In support of this hypothesis, a subpopulation of CD8+ T cells expressing the CXCR5 marker has been recently described to localize in B cell follicles and to stimulate B cells (37).…”