Impact of secondary TCR engagement on the heterogeneity of pathogen-specific CD8+T cell response during acute and chronic toxoplasmosis

Abstract

AbstractInitial TCR engagement of CD8+T cells results in T cell expansion, and these early events influence the generation of diverse effector and memory populations. During infection, some activated T cells re-encounter cognate antigen, but how these events influence local effector responses or formation of memory populations is unclear. To address this issue, OT-I T cells which express the Nur77-GFP reporter of TCR activation were paired withT. gondiithat express OVA to assess the impact of TCR activation on CD8+T cell responses. During acute infection, TCR stimulation in affected tissues correlated with parasite burden and was associated with markers of effector cells while Nur77-GFP-OT-I showed signs of effector memory potential. However, adoptive transfer of Nur77-GFP negative or positive OT-I from infected mice into naive recipients resulted in formation of similar memory populations. During the chronic stage of infection in the CNS, TCR activation was associated with large scale transcriptional changes and the acquisition of an effector T cell phenotype as well as the generation of a population of CD103+CD69+Trm like cells. However, while inhibition of parasite replication resulted in reduced effector responses it did not alter the Trm population. These data sets highlight the contribution of recent TCR activation on the phenotypic heterogeneity of the CD8+T cell response but suggest that this process has a limited impact on memory populations at acute and chronic stages of infection.Author SummaryCD8+T cells are important to control many acute and chronic infections, however the role that recent T cell receptor stimulation plays in the formation of ongoing T cell responses is unclear. Here, we utilize a genetic reporter of TCR stimulation and high parameter flow cytometry to characterize TCR-driven phenotypes of pathogen specific T cell responses to the parasiteToxoplasma gondiiduring acute and chronic infection in the periphery and central nervous system. This work demonstrates the importance of recent TCR stimulation in driving local effector CD8+T cell responses in peripheral tissues during infection, as well as the plasticity of the formation of memory T cells. Additionally, we utilize static and live imaging to investigate howToxoplasma gondiilife cycle impacts the ability to present antigen to CD8+T cells. These studies aid in our understanding of how effector and memory CD8+T cell responses are generated and maintained during an infection.