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

Author summaryFollowing priming, the ability of effector CD8(+) T cells to recognize class I restricted microbial antigens is 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, high parameter flow cytometry, and imaging to characterize TCR-driven phenotypes of pathogen specific T cell responses to the parasite Toxoplasma gondii during acute and chronic infection in the periphery and central nervous system. These data sets highlight the contribution of recent TCR activation on the phenotypic heterogeneity of the CD8(+) T cell response but suggest that T cell memory formation and maintenance is independent of recent TCR activation. Initial TCR engagement (priming) of naive CD8(+) T cells results in T cell expansion, and these early events influence the generation of diverse effector and memory populations. During infection, activated T cells can 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 with the parasite Toxoplasma gondii that expresses OVA to assess how secondary encounter with antigen influences 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, both Nur77-GFP(-) and Nur77-GFP(+) OT-I from acutely infected mice formed similar memory populations when transferred into naive mice. 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. While inhibition of parasite replication resulted in reduced effector responses it did not alter the Trm population. These data sets highlight that recent TCR activation contributes to 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.

Automated summary

The study characterizes the TCR-driven phenotypes of CD8(+) T cell responses to Toxoplasma gondii infection using genetic reporters, high parameter flow cytometry, and imaging techniques. The results demonstrate that recent TCR activation contributes to the phenotypic heterogeneity of the CD8(+) T cell response, but has limited impact on memory populations during acute and chronic stages of infection.