CXCR5+CD8+ T cells are a distinct functional subset with an antitumor activity

Abstract

CXCR5 mediates homing of both B and follicular helper T (TFH) cells into follicles of secondary lymphoid organs. We found that CXCR5+CD8+ T cells are present in human tonsils and follicular lymphoma, inhibit TFH-mediated B-cell differentiation, and exhibit strong cytotoxic activity. Consistent with these findings, adoptive transfer of CXCR5+CD8+ T cells into an animal model of lymphoma resulted in significantly greater antitumor activity than CXCR5−CD8+ T cells. Furthermore, RNA-Seq-based transcriptional profiling revealed a 77-gene signature unique to CXCR5+CD8+ T cells. The upregulated 33 genes among the 77-gene signature correlated with improved survival in follicular lymphoma patients. We also showed that CXCR5+CD8+ T cells could be induced and expanded ex vivo using IL-23 plus TGF-β, suggesting a possible strategy to generate these cells for clinical application. In summary, our study identified CXCR5+CD8+ T cells as a distinct T-cell subset with ability to suppress TFH-mediated B-cell differentiation, exert strong antitumor activity, and confer favorable prognosis in follicular lymphoma patients.

Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure

“…Interestingly, recent studies have better characterized a subset of CD8 + /CXCR5 + T cells with proliferative capacity and able to infiltrate B cell follicles and inflamed tissues in the presence of chronic antigen exposure and inflammation ( 129 , 131 , 136 – 143 ). This subset shows heterogeneous phenotype and gene expression profile depending on the pathogenic context, still it is distinct from the CXCR5 − counterpart pool and maintain cytotoxic properties ( 144 ). In addition of being part of the TCF-1 + /PD-1 int progenitor pool ( 129 , 145 ), these cells have been described as having variable levels of exhaustion and being similar to Tfh cells ( 20 , 108 , 129 , 131 , 141 , 146 – 149 ).…”

CXCR5gene expression in human lymph node CD8+T cells is regulated by DNA methylation and nucleosomal occupancy

“…fCD8s are associated with HIV and tumour control (16,18), but their differentiation conditions in humans are not known. Recent animal studies have defined the regulatory networks that govern the expression of CXCR5 in CD8 + T cells (16,17,22,23).…”

“…A small subset CXCR5 expressing CD8 + T cells called follicular CD8 + T cells (fCD8) has recently been described, to have the capacity to infiltrate B cell follicles and eliminate HIV infected cells or tumour cells (16)(17)(18). Human and animal studies have shown that the frequency of fCD8s inversely correlates with HIV or simian immunodeficiency virus (SIV) viral load (16,19,20), suggesting that increased infiltration of fCD8s in B cell follicles can result in enhanced immune control.…”

“…In addition, in the SIV model, CD8 + T depletion is associated with modest increase of SIV infected cells in B cell follicles (12), suggesting their involvement in mediating control of virus replication in the follicles. Moreover, in follicular lymphoma (FL), the second most frequent B-Cell lymphoma in adults (21), increased infiltration of CD8 + T cells into B cell follicles is associated with improved disease prognosis (18). Thus, detailed understanding of the regulatory mechanisms that govern the expression of CXCR5, the chemokine receptor required for CD8 + T cells migration to B cell follicles is highly relevant to the development of curative strategies for HIV and B cell lymphomas (18).…”

Identification and validation of an excellent prognosis subtype of muscle-invasive bladder cancer patients with intratumoral CXCR5 + CD8 + T cell abundance

“…17 In cases of B cell lymphoma, a trend of CXCR5 + CD8 + T cells directly targeting tumor cells was observed. 18 In HBV-related liver cancer, CXCR5 + CD8 + T cells are likely to be initially induced by viral responses, and then act on tumor cells. 19 As it is demonstrated in previous studies, CXCR5 + CD8 + T cell frequency is positively correlated with the overall survival of patients with various malignancies, including the malignancies mentioned above along with colorectal, 20 pancreas, 21 lung 22 and thyroid 23 cancer.…”