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

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 (CD8_CXCR5+ICOS+). These cells shared phenotypic features with follicular helper T (T_FH) 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-γ secretion, and common functional properties with intratumoral CD4⁺ T_FH 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 CD8_CXCR5+ICOS+ T cells and CD4⁺ T_FH cells. Benign lymphadenitis tissues (n = 8) were devoid of CD8_CXCR5+ICOS+ cells. Among the 35 B-cell lymphoma tissues analyzed, including follicular lymphomas (n = 13), diffuse large cell lymphomas (n = 12), marginal zone lymphomas (MZLs; n = 3), mantle cell lymphomas (n = 3), and chronic lymphocytic leukemias (n = 4), only 1 MZL sample contained CD8_CXCR5+ICOS+ cells. Lymphoma tumors with CD8_CXCR5+ICOS+ cells shared common histopathological features including residual germinal centers, and contained high amounts of activated CD8_CXCR5-ICOS+ cells. These data demonstrate a CD8 T-cell differentiation pathway leading to the acquisition of some T_FH similarities. They suggest a particular immunoediting process with global CD8 activation acting mainly, but not exclusively, in HL tumors.