Examining the induction, stability and function of IL-10 producing CD4+ T cells during experimental malaria infection

IL-10 is an important cytokine that plays a central role in regulating pro-inflammatory immune responses in many different infections and conditions (Couper et al. J. Immunology 2008). Thus, the outcome of numerous infections are, in part, determined by the level and timing of production of IL-10. This is particularly true during malaria infection where ablation of IL-10 can lead to the development of immunopathology and severe malarial disease.

We have shown that CD4+ T cells are the primary source of IL-10 in the spleen during experimental murine malaria infection (Couper et al. PLoS Pathogens 2008). Ex vivo analysis of the IL-10 producing CD4+ T cells indicated that they were functionally distinct from Th1, Th2, Th17 and regulatory Foxp3+ T cells, and as such they matched the description of adaptive regulatory T cells. The aims of this project are to use IL-10 and IFN-gamma reporter mice to (i) identify the pathways that promote differentiation of adaptive regulatory cells versus Th1 cells during malaria infection, (ii) to examine whether temporal production of IL-10 occurs by different cellular populations in lymphoid and non-lymphoid tissue during malaria infection, (iii) to define the primary cellular targets and functions of IL-10 during infection. In addition, we will examine the stability of the adaptive regulatory T cell phenotype throughout the course of malaria infection and examine whether IL-10 producing CD4+ T cells formed during a primary infection differentiate into long-lasting memory cells that modulate immune responses during secondary infection. The results of this project will significantly increase our understanding of how CD4+ T cell responses develop and self-regulate during malaria infection, which will have clear implications for the design of immunomodulatory treatments and vaccines for severe malarial disease.