title: Functional expression of CD137 (4-1BB) on T helper follicular cells.
abstract: CD137 (4-1BB) is a surface protein initially discovered to mark activated T lymphocytes. However, its broader expression pattern also encompasses activated NK cells, B cells and myeloid cells, including mature dendritic cells. In this study, we have immunostained for CD137 on paraffin-embedded lymphoid tissues including tonsils, lymph nodes, ectopic tertiary lymphoid tissue in Hashimoto thyroiditis and cancer. Surprisingly, immunostaining mainly decorated intrafollicular lymphocytes in the tissues analyzed, with only scattered staining in interfollicular areas. Moreover, pathologic lymphoid follicles in follicular lymphoma and tertiary lymphoid tissue associated with non-small cell lung cancer showed a similar pattern of immunostaining. Multispectral fluorescence cytometry demonstrated that CD137 expression was restricted to CD4+CXCR5+follicular T helper lymphocytes (TFHcells) in tonsils and lymph nodes. Short-term culture of lymph node cell suspensions in the presence of either an agonistic anti-CD137 monoclonal antibody (mAb) or CD137-ligand stimulated the functional upregulation of TFHcells in 3 out of 6 cases, as indicated by CD40L surface expression and cytokine production. As a consequence, immunostimulatory monoclonal antibodies targeting CD137 (such as urelumab and PF-05082566) should be expected to primarily act on this lymphocyte subset, thus modifying ongoing humoral immune responses in patients with autoimmune disease and cancer.
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain ; Oncology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.affiliation: Pathology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Jose I
authors.initials: JI
authors.lastname: Echeveste
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain ; Oncology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Rodriguez-Ruiz
authors.affiliation: Pathology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Solorzano
authors.affiliation: Oncology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Perez-Gracia
authors.affiliation: Pathology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Idoate
authors.affiliation: Oncology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lopez-Picazo
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain.
authors.forename: Alfonso R
authors.initials: AR
authors.lastname: Sanchez-Paulete
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Labiano
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain ; Oncology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Oñate
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Aznar
authors.affiliation: Pathology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Lozano
authors.affiliation: Division of Gene Therapy and Hepatology; Centre for Applied Medical Research ; Pamplona, Spain ; Oncology Department; University Clinic of Navarra ; Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
keywords: CD137 (4-1BB)v; T helper follicular cells; lymphoid follicle; tertiary lymphoid tissue