title: Phenotype, effector function, and tissue localization of PD-1-expressing human follicular helper T cell subsets.
abstract: BACKGROUND
  It is well established that PD-1 is expressed by follicular T cells but its function in regulation of human T helper cells has been unclear. We investigated the expression modality and function of PD-1 expressed by human T cells specialized in helping B cells.
  
  
  RESULTS
  We found that PD-1-expressing T cells are heterogeneous in PD-1 expression. We identified three different PD-1-expressing memory T cell subsets (i.e. PD-1(low)+, PD-1(medium)++, and PD-1(high)+++ cells). PD-1+++ T cells expressed CXCR5 and CXCR4 and were localized in the rim of germinal centers. PD-1+ or PD-1++ cells expressed CCR7 and were present mainly in the T cell area or other parts of the B cell follicles. Utilizing a novel antigen density-dependent magnetic sorting (ADD-MS) method, we isolated the three T cell subsets for functional characterization. The germinal center-located PD-1+++ T cells were most efficient in helping B cells and in producing IL-21 and CXCL13. Other PD-1-expressing T cells, enriched with Th1 and Th17 cells, were less efficient than PD-1+++ T cells in these capacities. PD-1+++ T cells highly expressed Ki-67 and therefore appear active in cell activation and proliferation in vivo. IL-2 is a cytokine important for proliferation and survival of the PD-1+++ T cells. In contrast, IL-21, while a major effector cytokine produced by the PD-1-expressing T helper cells, had no function in generation, survival, or proliferation of the PD-1-expressing helper T cells at least in vitro. PD-1 triggering has a suppressive effect on the proliferation and B cell-helping function of PD-1+++ germinal center T cells.
  
  
  CONCLUSIONS
  Our results revealed the phenotype and effector function of PD-1-expressing T helper cell subsets and indicate that PD-1 restrains the B cell-helping function of germinal center-localized T cells to prevent excessive antibody response.
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Center for Cancer Research, Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Hillsamer
authors.forename: Chang H
authors.initials: CH
authors.lastname: Kim
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D018189:Immunomagnetic Separation; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics; D014066:Palatine Tonsil / Q000473:pathology*; D019899:Paracrine Communication; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: C527276:CXCR4 protein, human; C095085:CXCR5 protein, human; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5