title: CD55 costimulation induces differentiation of a discrete T regulatory type 1 cell population with a stable phenotype.
abstract: Unlike other helper T cells, the costimulatory ligands responsible for T regulatory type 1 (Tr1) cell differentiation remain undefined. Understanding the molecular interactions driving peripheral Tr1 differentiation is important because Tr1s potently regulate immune responses by IL-10 production. In this study, we show that costimulation of human naive CD4(+) cells through CD97/CD55 interaction drives Tr1 activation, expansion, and function. T cell activation and expansion was equipotent with CD55 or CD28 costimulation; however, CD55 costimulation resulted in two IL-10-secreting populations. Most IL-10 was secreted by the minor Tr1 population (IL-10(high)IFN-γ(-)IL-4(-), <5% cells) that expresses Tr1 markers CD49b, LAG-3, and CD226. This Tr1 phenotype was not restimulated by CD28. However, on CD55 restimulation, Tr1s proliferated and maintained their differentiated IL-10(high) phenotype. The Tr1s significantly suppressed effector T cell function in an IL-10-dependent manner. The remaining (>95%) cells adopted a Th1-like IFN-γ(+) phenotype. However, in contrast to CD28-derived Th1s, CD55-derived Th1s demonstrated increased plasticity with the ability to coexpress IL-10 when restimulated through CD55 or CD28. These data identify CD55 as a novel costimulator of human Tr1s and support a role for alternative costimulatory pathways in determining the fate of the growing number of T helper populations. This study demonstrates that CD55 acts as a potent costimulator and activator of human naive CD4(+) cells, resulting in the differentiation of a discrete Tr1 population that inhibits T cell function in an IL-10-dependent manner and maintains the Tr1 phenotype upon restimulation.
authors.affiliation: Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham NG5 1PB, United Kingdom.
authors.forename: Ruhcha V
authors.initials: RV
authors.lastname: Sutavani
authors.forename: Richard G
authors.initials: RG
authors.lastname: Bradley
authors.forename: Judith M
authors.initials: JM
authors.lastname: Ramage
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Jackson
authors.forename: Lindy G
authors.initials: LG
authors.lastname: Durrant
authors.forename: Ian
authors.initials: I
authors.lastname: Spendlove
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D018106:CD28 Antigens / Q000276:immunology; D018958:CD55 Antigens / Q000276:immunology*; D002455:Cell Division; D002478:Cells, Cultured; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D038041:Lymphopoiesis; D043562:Receptors, G-Protein-Coupled; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
chemical_list: C095004:ADGRE5 protein, human; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D018958:CD55 Antigens; C508609:IL10 protein, human; D007376:Interleukin-2; D043562:Receptors, G-Protein-Coupled; D016753:Interleukin-10; D007371:Interferon-gamma