Surface expression of inhibitory (CTLA-4) and stimulatory (OX40) receptors by CD4+regulatory T cell subsets circulating in human malaria.
Several CD4+T cell subtypes contribute to immune homeostasis in malaria, but the markers that define the main suppressive T cell subsets induced by this infection remain largely unknown. Here we provide a detailed phenotypic characterization of immunoregulatory CD4+T cell populations in uncomplicated human malaria. We found an increased proportion of CD4+T cells expressing CTLA-4, OX40, GITR, TNFRII, and CD69 in acute-phase single-species infections with Plasmodium vivax, Plasmodium falciparum, or both. Such an increase was not proportional to parasite density in P. vivax infections, and did not persist after parasite clearance. Significantly, less than 10% of CD4+T cells expressing these regulatory molecules had the classical T regulatory (Treg) phenotype (CD4+CD25+CD127-FoxP3+). Two major Treg cell subpopulations, which together accounted for 19-23% of all Treg cells circulating in malaria patients, expressed surface receptors with opposing regulatory functions, either CTLA-4 or OX40. OX40+Treg cells outnumbered their CTLA-4+counterparts (1.8:1) during acute P. vivax infection, while a more balanced ratio (1.3:1) was observed following parasite clearance These data reveal new players in the complex CD4+Treg cell network that maintains immune homeostasis in malaria and suggest potential targets for therapeutic interventions to improve parasite-specific effector immune responses.
Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, Cidade Universitária, 05508-000, São Paulo, São Paulo, Brazil.
Raquel M
RM
Gonçalves-Lopes
Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, Cidade Universitária, 05508-000, São Paulo, São Paulo, Brazil.
Nathália F
NF
Lima
Division of Clinical Immunology and Allergy, Faculty of Medicine, University of São Paulo, Av. Dr. Arnaldo 455, Pinheiros, 01246-903, São Paulo, São Paulo, Brazil; Albert Einstein Hospital, Av. Albert Einstein 627, Jardim Leonor, 05652-000, São Paulo, São Paulo, Brazil.
Karina I
KI
Carvalho
Department of Parasitology, Microbiology and Immunology, Institute of Biological Sciences, Federal University of Juiz de Fora, Av. Lourenço Kelmer, Bairro Martelos, 36036-900, Juiz de Fora, Minas Gerais, Brazil.
Kézia K G
KK
Scopel
Division of Clinical Immunology and Allergy, Faculty of Medicine, University of São Paulo, Av. Dr. Arnaldo 455, Pinheiros, 01246-903, São Paulo, São Paulo, Brazil.
Esper G
EG
Kallás
Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, Cidade Universitária, 05508-000, São Paulo, São Paulo, Brazil. Electronic address: muferrei@usp.br.
Marcelo U
MU
Ferreira
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000032:analysis*; D005260:Female; D006706:Homeostasis; D006801:Humans; D016778:Malaria, Falciparum / Q000276:immunology / Q000473:pathology*; D016780:Malaria, Vivax / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D053262:Receptors, OX40 / Q000032:analysis*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D055815:Young Adult
D060908:CTLA-4 Antigen; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human
CTLA-4; Human malaria; Immunoregulation; OX-40; Treg cells