CD4+T cells display a spectrum of recall dynamics during re-infection with malaria parasites

Abstract

AbstractChildren in malaria-endemic regions can experience multiplePlasmodiuminfections over a short period of time, within vitroCD4+T cell recall responses becoming more regulatory with increasing age and exposure. This suggests that repeated infection qualitatively changes CD4+T cells, although the heterogeneity and dynamics of these responses await systematic analysisin vivo. Here, we examined TCR transgenic PbTII and polyclonal CD4+T cells duringPlasmodiumre-infection in mice, in conjunction with scRNA-seq/TCR-seq and spatial transcriptomics at near single-cell resolution. PbTII cells gave rise to multiple antigen-experienced states in different areas of the spleen after primary infection and antimalarial treatment, including ongoing GC responses and T-cell zone memory. Upon re-infection, Th1-memory PbTII cells initiated a rapid effector response prior to proliferating, while GC Tfh cells of the same antigen specificity were entirely refractory within the same organ. Transcriptome dynamic modelling and network analysis of Th1 recall revealed a biphasic wave of RNA processing that firstly preceded immune effector transcription, and later accompanied cellular proliferation. Importantly, Th1 recall constituted a partial facsimile of primary Th1 responses, with no unique genes amongst the small subset of those upregulated upon re-infection. Finally, we noted a similar spectrum of antigen-experienced states and recall dynamics by polyclonal CD4+T cells with diverse TCRs. Therefore, during re-infection withPlasmodium, persisting GC Tfh cells remained unaltered transcriptionally, Tcm/Tfh-like cells exhibited minimal proliferation, and Th1-memory cells displayed a rapid, proliferating IL-10-producing Tr1 response consistent with a shift towards immune-regulation. These data highlight a broad spectrum of simultaneous CD4+T cell responses that occur in the spleen during re-infection with malaria parasites.HighlightsSplenic TCR transgenic CD4+T cells are highly heterogeneous prior to re-infection.Persisting GC Tfh cells are refractory to re-activation during re-infection.Th1-memory cells rapidly upregulate RNA processing prior to effector function and proliferation.Th1-recall is an imperfect but faithful facsimile of primary Th1 responses.A spectrum of recall states is observed in polyclonal CD4+T cells with diverse TCRs.