Characterisation of anti-parasitic CD4+ T cell responses during malaria

Abstract

1 AbstractThe CD4 + T cell response during malaria is critical for control of Plasmodium infection.Unfortunately, this response is commonly dysfunctional or absent in individuals living in malaria endemic regions, and current vaccination efforts have been unable to effectively overcome these short comings. Therefore, a better understanding of host immune responses during Plasmodium infection is required if we are to improve vaccine efficacy and promote long-lived protective immunity. To improve our understanding of the CD4 + T cell response, we assessed changes in the transcriptional profile of these cells, over the course of Plasmodium falciparum infection, in volunteers who had not previously been exposed toPlasmodium, who were taking part in controlled human malaria infection (CHMI) studies.Bioinformatic analysis identified CXCL8 expression as a biomarker of sub-microscopic infection. Additionally, the degree of CXCL8 expression was indicative of initial parasite growth rate. We also identified the emergence of a significant regulatory profile in the CD4 + T cell population which developed with drug-mediated clearance of infection. This profile included checkpoint inhibitors PD-1, LAG-3, TIM-3, and CTLA-4. The degree of PD-1 expression on putative Tr1 (CD49b+ LAG-3+) cells negatively correlated with initial parasite growth rate. However, only PD-1 blockade affected antigen specific expression of the Tr1 cell related cytokines IFNγ and IL-10 by peripheral blood mononuclear cells (PBMCs) from CHMI study volunteers. Another transcriptional change following drug-mediated control was down-regulation of the master transcription factor BACH2. BACH2 plays an important role in T cell homeostasis and facilitates the stability and function of the FOXP3 + regulatory T (Treg) cell population while modulating effector T cell differentiation. Using transgenic mice with T cell specific BACH2 deficiency we showed that BACH2 was an important intrinsic factor in CD4 + T cells during cell differentiation in vitro. In the context of experimental malaria and a second parasitic infection, visceral leishmaniasis (VL), we showed that T cell-specific BACH2 modulated Th2, Th17 and Tfh cell differentiation, and suppressed effector CD4 + T cell responses. However, BACH2 was also important for the expansion and/or maintenance of splenic Treg cells during parasitic infection. Using pathway analysis to further assess the Plasmodium induced change in the transcriptional profile of CD4 + T cells we identified differential regulation of the IL-10 Abstract 42325972 2 signalling pathway after drug-mediated clearance of infection. In a number of parasitic infections, IL-10 signalling is primarily mediated by a FOXP3 -IL-10-producing regulatory CD4 + T (Tr1) cell subset. Tr1 cell frequency has been positively correlated with chronic malaria exposure in Ugandan children, and in mouse models of VL and malaria. We recently reported that Tr1 cells suppressed anti-parasitic immune responses, but also played a key role in preventing immunopathology. To i...