title: Strong impact of CD4+ Foxp3+ regulatory T cells and limited effect of T cell-derived IL-10 on pathogen clearance during Plasmodium yoelii infection.
abstract: It is well established that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play a crucial role in the course of different infectious diseases. However, contradictory results have been published regarding to malaria infection. In this study, we report that specific ablation of Foxp3(+) Tregs in Plasmodium yoelii-infected DEREG-BALB/c mice leads to an increase in T cell activation accompanied by a significant decrease in parasitemia. To better understand how Foxp3(+) Tregs orchestrate this phenotype, we used microarrays to analyze CD4(+)CD25(+)Foxp3(+) Tregs and CD4(+)CD25(-)Foxp3(-) T cells in the course of P. yoelii infection. Using this approach we identified genes specifically upregulated in CD4(+)CD25(+)Foxp3(+) Tregs in the course of infection, such as G-protein-coupled receptor 83 and Socs2. This analysis also revealed that both CD4(+)CD25(+)Foxp3(+) Tregs and CD4(+)CD25(-)Foxp3(-) T cells upregulate CTLA-4, granzyme B, and, more strikingly, IL-10 during acute blood infection. Therefore, we aimed to define the function of T cell-derived IL-10 in this context by Cre/loxP-mediated selective conditional inactivation of the IL-10 gene in T cells. Unexpectedly, IL-10 ablation in T cells exerts only a minor effect on parasite clearance, even though CD8(+) T cells are more strongly activated, the production of IFN-γ and TNF-α by CD4(+)CD25(-) T cells is increased, and the suppressive activity of CD4(+)CD25(+) Tregs is reduced upon infection. In summary, these results suggest that CD4(+)Foxp3(+) Tregs modulate the course of P. yoelii infection in BALB/c mice. Moreover, CD4(+) T cell-derived IL-10 affects T effector function and Treg activity, but has only a limited direct effect on parasite clearance in this model.
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Abel
authors.forename: Nadja
authors.initials: N
authors.lastname: Lückheide
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hansen
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008218:Lymphocytosis / Q000235:genetics / Q000276:immunology / Q000469:parasitology; D008288:Malaria / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010967:Plasmodium yoelii / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D016753:Interleukin-10