CXCR5 and ICOS expression identifies a CD8 T-cell subset with TFH features in Hodgkin lymphomas

Abstract

A better characterization of T-cell subsets in the microenvironment of classical Hodgkin lymphoma (cHL) would help to develop immunotherapies. Using multicolor flow cytometry, we identified in 6 of 43 cHL tissue samples a previously unrecognized subset of CD8 T cells coexpressing CXCR5 and inducible T-cell costimulator (ICOS) molecules (CD8CXCR51ICOS1). These cells shared phenotypic features with follicular helper T (TFH) cells including low CCR7 expression together with high expression of B-cell lymphoma-6, programmed cell death 1, B and T lymphocyte attenuator, CD200, and OX40. They had deficient cytotoxicity, low interferon-g secretion, and common functional properties with intratumoral CD41 TFH cells, such as production of interleukin-4 (IL-4), IL-21, CXCL13, and capacity to sustain B cells. Gene profiling analysis showed a significant similarity between the signatures of CD8CXCR51ICOS1 T cells and CD41 TFH cells. Benign lymphadenitis tissues (n 5 8) were devoid of CD8CXCR51ICOS1 cells. Among the 35 B-cell lymphoma tissues analyzed, including follicular lymphomas (n 5 13), diffuse large cell lymphomas (n 5 12), marginal zone lymphomas (MZLs; n 5 3), mantle cell lymphomas (n 5 3), and chronic lymphocytic leukemias (n 5 4), only 1 MZL sample contained CD8CXCR51ICOS1 cells. Lymphoma tumors with CD8CXCR51ICOS1 cells shared common histopathological features including residual germinal centers, and contained high amounts of activated CD8CXCR52ICOS1 cells. These data demonstrate a CD8 T-cell differentiation pathway leading to the acquisition of some TFH similarities. They suggest a particular immunoediting process with global CD8 activation acting mainly, but not exclusively, in HL tumors.