title: The spleen CD4+ T cell response to blood-stage Plasmodium chabaudi malaria develops in two phases characterized by different properties.
abstract: The pivotal role of spleen CD4(+) T cells in the development of both malaria pathogenesis and protective immunity makes necessary a profound comprehension of the mechanisms involved in their activation and regulation during Plasmodium infection. Herein, we examined in detail the behaviour of non-conventional and conventional splenic CD4(+) T cells during P. chabaudi malaria. We took advantage of the fact that a great proportion of CD4(+) T cells generated in CD1d(-/-) mice are I-A(b)-restricted (conventional cells), while their counterparts in I-A(b-/-) mice are restricted by CD1d and other class IB major histocompatibility complex (MHC) molecules (non-conventional cells). We found that conventional CD4(+) T cells are the main protagonists of the immune response to infection, which develops in two consecutive phases concomitant with acute and chronic parasitaemias. The early phase of the conventional CD4(+) T cell response is intense and short lasting, rapidly providing large amounts of proinflammatory cytokines and helping follicular and marginal zone B cells to secrete polyclonal immunoglobulin. Both TNF-α and IFN-γ production depend mostly on conventional CD4(+) T cells. IFN-γ is produced simultaneously by non-conventional and conventional CD4(+) T cells. The early phase of the response finishes after a week of infection, with the elimination of a large proportion of CD4(+) T cells, which then gives opportunity to the development of acquired immunity. Unexpectedly, the major contribution of CD1d-restricted CD4(+) T cells occurs at the beginning of the second phase of the response, but not earlier, helping both IFN-γ and parasite-specific antibody production. We concluded that conventional CD4(+) T cells have a central role from the onset of P. chabaudi malaria, acting in parallel with non-conventional CD4(+) T cells as a link between innate and acquired immunity. This study contributes to the understanding of malaria immunology and opens a perspective for future studies designed to decipher the molecular mechanisms behind immune responses to Plasmodium infection.
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, São Paulo, Brazil. sandrammuxel@gmail.com
authors.forename: Sandra Marcia
authors.initials: SM
authors.lastname: Muxel
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Freitas do Rosário
authors.forename: Cláudia Augusta
authors.initials: CA
authors.lastname: Zago
authors.forename: Sheyla Inés
authors.initials: SI
authors.lastname: Castillo-Méndez
authors.forename: Luiz Roberto
authors.initials: LR
authors.lastname: Sardinha
authors.forename: Sérgio Marcelo
authors.initials: SM
authors.lastname: Rodriguez-Málaga
authors.forename: Niels Olsen Saraiva
authors.initials: NO
authors.lastname: Câmara
authors.forename: José Maria
authors.initials: JM
authors.lastname: Álvarez
authors.forename: Maria Regina D'Império
authors.initials: MR
authors.lastname: Lima
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D055610:Antigens, CD1d / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018512:Parasitemia / Q000276:immunology* / Q000473:pathology; D016788:Plasmodium chabaudi / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000913:Antibodies, Protozoan; D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma