The Spleen CD4+ T Cell Response to Blood-Stage Plasmodium chabaudi Malaria Develops in Two Phases Characterized by Different Properties.

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 nonconventional 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. [ABSTRACT FROM AUTHOR]