Memory CD8 + T cells exhibit tissue imprinting and non‐stable exposure‐dependent reactivation characteristics following blood‐stage Plasmodium berghei ANKA infections

From Wiley via Jisc Publications RouterHistory: received 2020-11-02, rev-recd 2021-08-09, accepted 2021-08-13, pub-electronic 2021-08-27Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): G0900487, MR/R010099/1Abstract: Experimental cerebral malaria (ECM) is a severe complication of Plasmodium berghei ANKA (PbA) infection in mice, characterized by CD8+ T‐cell accumulation within the brain. Whilst the dynamics of CD8+ T‐cell activation and migration during extant primary PbA infection have been extensively researched, the fate of the parasite‐specific CD8+ T cells upon resolution of ECM is not understood. In this study, we show that memory OT‐I cells persist systemically within the spleen, lung and brain following recovery from ECM after primary PbA‐OVA infection. Whereas memory OT‐I cells within the spleen and lung exhibited canonical central memory (Tcm) and effector memory (Tem) phenotypes, respectively, memory OT‐I cells within the brain post‐PbA‐OVA infection displayed an enriched CD69+CD103− profile and expressed low levels of T‐bet. OT‐I cells within the brain were excluded from short‐term intravascular antibody labelling but were targeted effectively by longer‐term systemically administered antibodies. Thus, the memory OT‐I cells were extravascular within the brain post‐ECM but were potentially not resident memory cells. Importantly, whilst memory OT‐I cells exhibited strong reactivation during secondary PbA‐OVA infection, preventing activation of new primary effector T cells, they had dampened reactivation during a fourth PbA‐OVA infection. Overall, our results demonstrate that memory CD8+ T cells are systemically distributed but exhibit a unique phenotype within the brain post‐ECM, and that their reactivation characteristics are shaped by infection history. Our results raise important questions regarding the role of distinct memory CD8+ T‐cell populations within the brain and other tissues during repeat Plasmodium infections