title: Long-Lived CD4+IFN-γ+ T Cells rather than Short-Lived CD4+IFN-γ+IL-10+ T Cells Initiate Rapid IL-10 Production To Suppress Anamnestic T Cell Responses during Secondary Malaria Infection.
abstract: CD4+T cells that produce IFN-γ are the source of host-protective IL-10 during primary infection with a number of different pathogens, including Plasmodium spp. The fate of these CD4+IFN-γ+IL-10+T cells following clearance of primary infection and their subsequent influence on the course of repeated infections is, however, presently unknown. In this study, utilizing IFN-γ-yellow fluorescent protein (YFP) and IL-10-GFP dual reporter mice, we show that primary malaria infection-induced CD4+YFP+GFP+T cells have limited memory potential, do not stably express IL-10, and are disproportionately lost from the Ag-experienced CD4+T cell memory population during the maintenance phase postinfection. CD4+YFP+GFP+T cells generally exhibited a short-lived effector rather than effector memory T cell phenotype postinfection and expressed high levels of PD-1, Lag-3, and TIGIT, indicative of cellular exhaustion. Consistently, the surviving CD4+YFP+GFP+T cell-derived cells were unresponsive and failed to proliferate during the early phase of secondary infection. In contrast, CD4+YFP+GFP-T cell-derived cells expanded rapidly and upregulated IL-10 expression during secondary infection. Correspondingly, CD4+T cells were the major producers within an accelerated and amplified IL-10 response during the early stage of secondary malaria infection. Notably, IL-10 exerted quantitatively stronger regulatory effects on innate and CD4+T cell responses during primary and secondary infections, respectively. The results in this study significantly improve our understanding of the durability of IL-10-producing CD4+T cells postinfection and provide information on how IL-10 may contribute to optimized parasite control and prevention of immune-mediated pathology during repeated malaria infections.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Villegas-Mendez
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Colette A
authors.identifier: 0000-0003-1215-312X
authors.initials: CA
authors.lastname: Inkson
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Tovah N
authors.identifier: 0000-0002-8107-2836
authors.initials: TN
authors.lastname: Shaw
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Strangward
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom kevin.couper@manchester.ac.uk ana.villegas-mendez@manchester.ac.uk.
authors.forename: Kevin N
authors.identifier: 0000-0003-4659-8960
authors.initials: KN
authors.lastname: Couper
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology / Q000637:transplantation; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D007156:Immunologic Memory; D000068884:Immunosenescence; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010961:Plasmodium / Q000276:immunology*
chemical_list: D016753:Interleukin-10; D007371:Interferon-gamma