title: Protective effector memory CD4 T cells depend on ICOS for survival.
abstract: Memory CD4 T cells play a vital role in protection against re-infection by pathogens as diverse as helminthes or influenza viruses. Inducible costimulator (ICOS) is highly expressed on memory CD4 T cells and has been shown to augment proliferation and survival of activated CD4 T cells. However, the role of ICOS costimulation on the development and maintenance of memory CD4 T cells remains controversial. Herein, we describe a significant defect in the number of effector memory (EM) phenotype cells in ICOS(-/-) and ICOSL(-/-) mice that becomes progressively more dramatic as the mice age. This decrease was not due to a defect in the homeostatic proliferation of EM phenotype CD4 T cells in ICOS(-/-) or ICOSL(-/-) mice. To determine whether ICOS regulated the development or survival of EM CD4 T cells, we utilized an adoptive transfer model. We found no defect in development of EM CD4 T cells, but long-term survival of ICOS(-/-) EM CD4 T cells was significantly compromised compared to wild-type cells. The defect in survival was specific to EM cells as the central memory (CM) ICOS(-/-) CD4 T cells persisted as well as wild type cells. To determine the physiological consequences of a specific defect in EM CD4 T cells, wild-type and ICOS(-/-) mice were infected with influenza virus. ICOS(-/-) mice developed significantly fewer influenza-specific EM CD4 T cells and were more susceptible to re-infection than wild-type mice. Collectively, our findings demonstrate a role for ICOS costimulation in the maintenance of EM but not CM CD4 T cells.
authors.affiliation: Committee on Immunology & Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Tamson V
authors.initials: TV
authors.lastname: Moore
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Clay
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Ferreira
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Williams
authors.forename: Magdalena
authors.initials: M
authors.lastname: Rogozinska
authors.forename: Judy L
authors.initials: JL
authors.lastname: Cannon
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Shilling
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Marzo
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007156:Immunologic Memory / Q000235:genetics* / Q000502:physiology; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D009980:Influenza A virus / Q000502:physiology; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011506:Proteins; D015847:Interleukin-4