CD4 T Cells from Malaria-Nonexposed Individuals Respond to the CD36-Binding Domain ofPlasmodium falciparumErythrocyte Membrane Protein-1 via an MHC Class II-TCR-Independent Pathway

Abstract

We have studied the human CD4 T cell response to a functionally conserved domain of Plasmodium falciparum erythrocyte membrane protein-1, cysteine interdomain region-1α (CIDR-1α). Responses to CIDR-1α were striking in that both exposed and nonexposed donors responded. The IFN-γ response to CIDR-1α in the nonexposed donors was partially independent of TCR engagement of MHC class II and peptide. Contrastingly, CD4 T cell and IFN-γ responses in malaria-exposed donors were MHC class II restricted, suggesting that the CD4 T cell response to CIDR-1α in malaria semi-immune adults also has a TCR-mediated component, which may represent a memory response. Dendritic cells isolated from human peripheral blood were activated by CIDR-1α to produce IL-12, IL-10, and IL-18. IL-12 was detectable only between 6 and 12 h of culture, whereas the IL-10 continued to increase throughout the 24-h time course. These data strengthen previous observations that P. falciparum interacts directly with human dendritic cells, and suggests that the interaction between CIDR-1α and the host cell may be responsible for regulation of the CD4 T cell and cytokine responses to P. falciparum-infected erythrocytes reported previously.

Inhibition of Dendritic Cell Maturation by Malaria Is Dose Dependent and Does Not RequirePlasmodium falciparumErythrocyte Membrane Protein 1

“…In this study, human monocyte-derived DCs showed a modest increase in expression of maturation markers in the presence of low-dose iRBCs and were subsequently able to stimulate and IL-18 (26). iRBCs have also been found to activate human plasmacytoid DCs (32), possibly through the action of hemozoin (7), which appears to target P. falciparum DNA to intracellular Toll-like receptor 9 receptors (30).…”

The role of leukocytes bearing Natural Killer Complex receptors and Killer Immunoglobulin-like Receptors in the immunology of malaria

“…By contrast, however, a number of subsequent studies using similar assays reported that NK cells were the main source of IFNg [36,37,38 ]. Furthermore, naïve ab-T cells might also contribute to early IFNg responses, their malaria reactivity in non-exposed donors being proposed to result either from reactivation of polyclonal memory populations primed to cross-reactive antigens [39] or by interaction with parasite-encoded polyclonal activating ligands [40]. Thus, the identity of the dominant sources of innate IFNg remained unclear, with the relative contribution of various cell types to parasite-elicited early IFNg responses not comparatively assessed.…”

Signal transduction in Plasmodium-Red Blood Cells interactions and in cytoadherence

“…Interestingly, cytoadherence of infected erythrocyte is also regulated by host signalling responses and Plasmodium falciparum proteins such as PfEMP1 binding to CD36 or ICAM-1 host receptors can modulate dendridic cells, monoycytes, endothelium and T cells (Urban et al 1999, Ndungu et al 2006, Chakravorty et al 2008, Langhorne et al 2008) in addition to soluble mediators. Inhibitors of TNF (tumor necrosis factor) also reduced infected erythrocyte cytoadherence (Wassmer et al 2006b, Chakravorty et al 2008 and comparison of murine malaria strains indicates that host immunological responses such as TNF secretion, T cell activation and pro-inflammatory cytokine activation lead to differences in parasite growth or death (Wykes and Good 2008).…”