title: The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection.
abstract: Blood-stage Plasmodium chabaudi chabaudi AS infection requires cell- and Ab-mediated immunity to control acute and persistent infection, respectively. ICOS regulates CD4(+) T cell activation and promotes the induction of follicular Th (TFH) cells, CD4(+) T cells that support B cell affinity maturation within germinal centers (GCs), resulting in the production of high-affinity Abs. In this article, we demonstrate that, in response to P. c. chabaudi AS infection, the absence of ICOS resulted in an enhanced Th1 immune response that reduced peak parasitemia. Despite the absence of ICOS, CD4(+) T cells were capable of expressing PD-1, B cell lymphoma 6, and CXCR5 during early infection, indicating TFH development was not impaired. However, by day 21 postinfection, Icos(-/-) mice accumulated fewer splenic TFHs compared with Icos(+/+) mice, leading to substantially fewer GC B cells and a decrease in affinity, but not production, of parasite-specific isotype-switched Abs. Moreover, treatment of mice with anti-ICOS ligand Abs to modulate ICOS-ICOS ligand signaling revealed a requirement for ICOS in TFH differentiation only after day 6 postinfection. Ultimately, the quality and quantity of isotype-switched Abs produced in Icos(-/-) mice declined over time, resulting in impaired control of persistent parasitemia. Collectively, these data suggest ICOS is not required for TFH induction during P. c. chabaudi AS infection or production of isotype-switched Abs, but it is necessary for maintenance of a sustained high-affinity, protective Ab response.
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wikenheiser
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
authors.forename: Debopam
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
authors.forename: Brian
authors.initials: B
authors.lastname: Kennedy
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 jstumhofer@uams.edu.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Stumhofer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016788:Plasmodium chabaudi; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein