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-Ab-restricted (conventional cells), while their counterparts in I-Ab-/- 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.
Highlights
Malaria, the infectious disease caused by Plasmodium parasites, is a major global health problem that is responsible for the death of over a million people every year [1]
I-Ab-restricted CD4+ T cells are required for the control of parasitaemia during the early and late P. chabaudi infection To evaluate the protective role of CD1d- and I-Ab-restricted
Mice developed a significantly higher first peak and prominent recrudescent peaks compared to WT mice. These mice were unable to eliminate the parasite and around 50% were dead one month after infection. These results indicate that parasite control during early and late P. chabaudi malaria is dependent on IAb-restricted CD4+ T cells, whereas the contribution of CD1drestricted CD4+ T cells is modest and limited to the second parasitaemia peak
Summary
The infectious disease caused by Plasmodium parasites, is a major global health problem that is responsible for the death of over a million people every year [1]. Humans with no previous experience of malaria almost invariably develop a febrile illness that may become severe and lead to death. Because many of the features of severe malaria are similar to those of sepsis [3], over-vigorous responses to parasites have been implicated in the aetiology of these syndromes [4,5]. Exposure to one or two malaria infections appears to be sufficient to induce complete protection from severe illness and death [8], while sterile immunity to malaria parasites is probably never achieved
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