title: PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival.
abstract: To determine the biological and clinical relevance of programmed death 1 (PD-1) in follicular lymphoma (FL), we characterized PD-1(+) T-cell subsets and assessed their biological function as well as potential clinical impact. We found that PD-1 is expressed on intratumoral CD4(+) T cells with both bright and dim intensity, representing two different sub-populations of cells. By immunohistochemistry, we found that CD4(+)PD-1(high) T cells predominantly reside in the lymph node follicles, while PD-1(low) T cells are mainly located in an interfollicular pattern. Intratumoral CD4(+)PD-1(high) T cells have a TFH cell phenotype, express CXCR5, secrete IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4(+)PD-1(low) T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4(+)PD-1(high) T cells actively supported B-cell growth, while CD4(+)PD-1(low) T cells displayed a reduced cytokine production and cell-signal transduction. Clinically, we observed that the numbers of CD4(+) or CD8(+)PD-1(low) T cells significantly correlate with a reduced overall survival in FL patients (P=0.007 and 0.04 respectively; n=32). In contrast, the number of CD4(+)PD-1(high) T cells was not associated with patient outcome. Taken together, these results indicated that PD-1 expression defines two sub-populations with distinct functions that differentially impact patient outcome in FL.
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Z-Z
authors.initials: ZZ
authors.lastname: Yang
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Grote
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Ziesmer
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Xiu
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Novak
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Ansell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008224:Lymphoma, Follicular / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis* / Q000235:genetics; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology*
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor