title: IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.
abstract: CD4 T cells are required to fight malaria infection by promoting both phagocytic activity and B cell responses for parasite clearance. In Plasmodium chabaudi infection, one specific CD4 T cell subset generates anti-parasitic IFN-γ and the antibody-promoting cytokine, IL-21. To determine the lineage of these multifunctional T cells, we followed IFN-γ+ effector T cells (Teff) into the memory phase using Ifng-reporter mice. While Ifng+ Teff expanded, the level of the Th1 lineage-determining transcription factor T-bet only peaked briefly. Ifng+ Teff also co-express ICOS, the B cell area homing molecule CXCR5, and other Tfh lineage-associated molecules including Bcl6, the transcription factor required for germinal center (GC) T follicular helper cells (Tfh) differentiation. Because Bcl6 and T-bet co-localize to the nucleus of Ifng+ Teff, we hypothesized that Bcl6 controls the Tfh-like phenotype of Ifng+ Teff cells in P. chabaudi infection. We first transferred Bcl6-deficient T cells into wildtype hosts. Bcl6-deficient T cells did not develop into GC Tfh, but they still generated CXCR5+ IFN-γ+ IL-21+ IL-10+ Teff, suggesting that this predominant population is not of the Tfh-lineage. IL-10 deficient mice, which have increased IFN-γ and T-bet expression, demonstrated expansion of both IFN-γ+ IL-21+ CXCR5+ cells and IFN-γ+ GC Tfh cells, suggesting a Th1 lineage for the former. In the memory phase, all Ifng+ T cells produced IL-21, but only a small percentage of highly proliferative Ifng+ T cells maintained a T-bethi phenotype. In chronic malaria infection, serum IFN-γ correlates with increased protection, and our observation suggests Ifng+ T cells are maintained by cellular division. In summary, we found that Ifng+ T cells are not strictly Tfh derived during malaria infection. T cells provide the host with a survival advantage when facing this well-equipped pathogen, therefore, understanding the lineage of pivotal T cell players will aid in the rational design of an effective malaria vaccine.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Carpio
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Opata
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Marelle E
authors.initials: ME
authors.lastname: Montañez
authors.affiliation: Center for Human Immunobiology of Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Pinaki P
authors.initials: PP
authors.lastname: Banerjee
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Robin
authors.initials: R
authors.lastname: Stephens
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000502:physiology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis / Q000502:physiology*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016788:Plasmodium chabaudi / Q000472:pathogenicity*; D051560:Proto-Oncogene Proteins c-bcl-6; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D007371:Interferon-gamma; D000098546:Interleukin-21