Murine Malaria Is Exacerbated by CTLA-4 Blockade

Abstract

Cytolytic T lymphocyte-associated Ag-4 (CD152) is a negatively regulating molecule, which is primarily expressed on T cells following their activation. In this study, we have examined the role of CTLA-4 expression in experimental blood-stage malaria. Similar to human malaria, CTLA-4 is expressed on CD4+ T cells of C57BL/6 mice after infection with Plasmodium berghei. A kinetic analysis revealed that CTLA-4 expression was increased on day 5 postinfection and reached a peak on day 9 postinfection, when almost 10% of splenic CD4+ T cells expressed CTLA-4. Blockade of CTLA-4 in vivo by a specific mAb and subsequent challenge with P. berghei caused neurological signs reminiscent of murine cerebral malaria and earlier death. Histologic examination of brain sections from anti-CTLA-4-treated mice revealed pathologic changes such as hemorrhages and edema, which were absent in control mice. Furthermore, treatment with anti-CTLA-4 also reversed the extensive loss of CD4+ T cells and the suppressed T cell response occurring during blood-stage malaria. Our data suggest that CTLA-4 expression prevents immune pathology by restricting T cell activation during malaria. They also indicate that the development of cerebral malaria is mediated by a failure to down-regulate T cell activation.

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

“…found that blockade of CTLA-4 led to enhanced immune pathology triggered by T cells producing proinflammatory cytokines (13,14). This supports the idea that the rapid induction of CTLA-4 during the blood stage of a PbA infection is a means to counterregulate the strong and polarized activation of the TH1 arm of the immune system to prevent immune pathology.…”

Limited Role of CD4+Foxp3+ Regulatory T Cells in the Control of Experimental Cerebral Malaria

“…Several studies have shown that during experimental malaria infection different regulatory mechanisms are triggered to avoid overwhelming pathology, such as production of IL-10 and TGF-ß (35,36). We have found that the negative costimulators CTLA-4 and BTLA expressed on T cells play a critical role during PbA infection by dampening the immune response (11)(12)(13). Recently, it was found that CTLA-4 is not only expressed by Foxp3 ϩ T reg constitutively, but is also critical for their function (37).…”

“…In light of the present study and our previous work, in which we demonstrate that during experimental malaria many more cells are CTLA-4 ϩ CD4 ϩ Foxp3 Ϫ T cells than CD4 ϩ Foxp3 ϩ T reg , it is tempting to speculate that counterregulatory mechanisms on activated T eff such as CTLA-4 induction represent a more suitable mechanism to control a rapidly evolving pathology (11,38). However, we cannot exclude the possibility that the exacerbation of pathology by anti-CTLA-4 treatment during PbA malaria (11,12) is a consequence of a functional restriction of CTLA-4 on both activated T eff and T reg .…”

“…Various studies clearly demonstrated a role for T cells secreting proinflammatory cytokines for the genesis of CM (7)(8)(9)(10). We recently found that T cell activation during malaria is accompanied by an increased expression of the negative costimulators CTLA-4 (11,12) and B and T lymphocyte attenuator (BTLA) (13). Both of these were shown to modulate T cell function during PbA infection.…”

The role of Vitamin D in malaria

“…CTLA-4-positive cells are elevated in acute P. falciparum and vivax malarias in humans [66][67][68]. Murine malaria is exacerbated by a CTLA-4 blockade, which induces higher parasitemia than in controls [69][70][71]. These findings suggest that CTLA-4 expression restricts pathogen-specific T-cell responses in malaria.…”