Decreasing initial stimulation increases generation of early effector cells that survive the contraction phase in malaria infection (MPF2P.754)

Abstract

Abstract CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing malaria vaccines is understanding generation of memory from effector T cells (Teff) in chronic infection. We use a transgenic mouse model with T cells specific for the Merozoite Surface Protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three Teff (CD127-) subsets representing progressive activation. The earliest observed subset (CD62LhiCD27+) divides first, and maintains memory gene expression. An intermediate (CD62LloCD27+) effector subset has more multi-cytokine producing T cells and a terminal phenotype, including expression of PD-1 and Fas. Fully activated (CD62LloCD27-) late effector cells contain fewer cytokine+ and more AnnexinVhi apoptotic cells. Using an adoptive transfer system, we show the ability of CD62Lhi Teff to generate the terminal Teff subsets but also to survive the contraction phase better than the CD62Llo subsets. Furthermore, we show that progression towards terminal differentiation increases with duration of infection, but is inhibited by IL-2, which promotes expansion but not progression. Therefore, we have defined markers of progressive activation of CD4 Teff at the peak of malaria infection, and shown that CD127-CD62Lhi Teff survive the contraction phase. Therefore, antigen and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive T cell contraction in malaria infection.