Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

Abstract

In malaria, CD4 Th1 and T follicular helper (TFH) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T‐cell subsets are critical to hamper pathology. Yet the antigen‐presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood‐stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins. Immunodominance is shaped differently whether blood stage is preceded or not by liver stage, but the same ETRAMP‐specific dominant response develops in both contexts. In naïve mice and at the onset of cerebral malaria, CD8α+ dendritic cells (cDC1) are superior to other DC subsets for MHC II presentation of the ETRAMP epitope. Using in vivo depletion of cDC1, we show that cDC1 promote parasite‐specific Th1 cells and inhibit the development of IL‐10+ CD4 T cells. This work profiles the P. berghei blood‐stage MHC II immunopeptidome, highlights the potency of cDC1 to present malaria antigens on MHC II, and reveals a major role for cDC1 in regulating malaria‐specific CD4 T‐cell responses.

Identification, molecular characterization and expression of aminopeptidase N-1 (APN-1) from Anopheles stephensi in SF9 cell line as a candidate molecule for developing a vaccine that interrupt malaria transmission

“…Therefore, for designing an effective recombinant immunogenic vaccine, considering and evaluating the prevalence of an allele in the target area is crucial [49]. Draheim et al study disclosed that the presentation of malaria antigen by MHC-II on dendritic cell is particularly important in induction of an effective immune response [50]. According to the in silico analysis, it is predicted that nine antigenic peptides have the best scores for perfect processing and presentation ability with the DQA10102-DQB10602 and DR B1 alleles and those could be considered as candidates for developing a recombinant subunit vaccine (Additional file 3) [51].…”

A virus hosted in malaria-infected blood protects against T cell-mediated inflammatory diseases by impairing DC function in a type I IFN-dependent manner

“…It has now become clear that IL-12p35 65 , IFN-γ and IL-17 66 are dispensable for the development of MOG-induced EAE while the key pathogenic cytokines are GM-CSF produced by CD4 + Th cells and IL-23, which may be produced by multiple sources 66,67 . Also, in contrast to ECM pathology in which cDC are required for the priming and polarization of Th1 CD4 + T cells [49][50][51] , cDC are not necessary for the priming of encephalitogenic CD4 + Th cells in MOG protein-induced EAE 68 and mice lacking cDC even display an aggravated disease 69 . Based on this, we propose that LDV-mediated protection against EAE is due to the global effect of IFN-I signaling, which inhibits IL-23 production by several different cell types of the dLN, including cDC, and that this prevents the differentiation of GM-CSF-secreting CD4 + T cells.…”

“…To study how LDV impedes the Th1 CD4 + T cell response, we analyzed splenic conventional DC (cDC), which are primarily responsible for Th1 priming and polarization in this context [49][50][51] . Two days following Pb ANKA / LDV co-infection, we observed a strong reduction in the proportion and numbers of total CD11c + MHCII + cDC, which was not observed in Ifnar1 KO mice ( Fig.…”

Current Challenges in the Identification of Pre-Erythrocytic Malaria Vaccine Candidate Antigens

“…Although the protection was relatively long and protected from a L. donovani challenge as well, sterile protection was not achieved (128). More recently, a survey on the MHC-II immunopeptidome was conducted on murine blood-stage malaria, generating a list of 14 MHC-II ligands presented by cDC1 dendritic cells, which included the blood-stage vaccine candidates AMA1 and MSP1 (129).…”