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Antigen-exhausted CD4+ T cells deviate towards multiple states of anergy
Antigen-exhausted CD4+ T cells deviate towards multiple states of anergy
Persistent antigen presentation by tumor cells and during chronic infections functionally impairs T cells over time, limiting progress of adoptive T cell therapies for such diseases. To address how different kinetics and dosage of antigen presentation affect CD4+ T cells in the absence of confounding pathologies of chronic infections, we followed TCR transgenic T cells transferred into antigen-transgenic recipients. There they received either transient or chronic TCR signals of varying strengths. We show that CD4+ T cells exposed to different levels of persisting antigen presentation display phenotypes with varying kinetics and consequences. Chronically antigen-exposed CD4+ T cells show impaired cytokine production upon re-stimulation, dose-dependent upregulation of exhaustion-, anergy-, and Tfh-associated markers and transcription factors. Continuous antigen presentation was sensed by the T cells, as indicated by Nur77-driven GFP-reporter expression and NFATc1 nuclear translocation, even at the highest dose where the TCR and LAT are chronically downregulated. When challenged, signaling pathways respond to strong TCR signals with Ca2+ fluxes being the most robust one while the MAPK and Akt pathways were more easily tuned by persisting antigen. The cells' transcriptional profiles reflected the qualitative and quantitative changes in antigen presentation by dose-dependent upregulation of exhaustion, anergy- and Tfh-associated, as well as downregulation of memory-associated genes. Comparisons with naturally occurring anergic and LCMV clone13-exhausted CD4+ T cells highlighted a common transcriptomic signature describing antigen-induced T cell anergy and exhaustion. Despite upregulation of Tfh-associated markers, antigen-exhausted CD4+ T cells lost their ability to provide help to B cells over time. Our results demonstrate that dose and timing of antigen presentation beyond the expansion phase reveal the plasticity of CD4+ T cells and determine their range of dysfunctionalities within an otherwise sterile environment.
T cell exhaustion, anergy, CD4+ T cells
Trefzer, Anne
2020
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Trefzer, Anne (2020): Antigen-exhausted CD4+ T cells deviate towards multiple states of anergy. Dissertation, LMU München: Faculty of Medicine
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Abstract

Persistent antigen presentation by tumor cells and during chronic infections functionally impairs T cells over time, limiting progress of adoptive T cell therapies for such diseases. To address how different kinetics and dosage of antigen presentation affect CD4+ T cells in the absence of confounding pathologies of chronic infections, we followed TCR transgenic T cells transferred into antigen-transgenic recipients. There they received either transient or chronic TCR signals of varying strengths. We show that CD4+ T cells exposed to different levels of persisting antigen presentation display phenotypes with varying kinetics and consequences. Chronically antigen-exposed CD4+ T cells show impaired cytokine production upon re-stimulation, dose-dependent upregulation of exhaustion-, anergy-, and Tfh-associated markers and transcription factors. Continuous antigen presentation was sensed by the T cells, as indicated by Nur77-driven GFP-reporter expression and NFATc1 nuclear translocation, even at the highest dose where the TCR and LAT are chronically downregulated. When challenged, signaling pathways respond to strong TCR signals with Ca2+ fluxes being the most robust one while the MAPK and Akt pathways were more easily tuned by persisting antigen. The cells' transcriptional profiles reflected the qualitative and quantitative changes in antigen presentation by dose-dependent upregulation of exhaustion, anergy- and Tfh-associated, as well as downregulation of memory-associated genes. Comparisons with naturally occurring anergic and LCMV clone13-exhausted CD4+ T cells highlighted a common transcriptomic signature describing antigen-induced T cell anergy and exhaustion. Despite upregulation of Tfh-associated markers, antigen-exhausted CD4+ T cells lost their ability to provide help to B cells over time. Our results demonstrate that dose and timing of antigen presentation beyond the expansion phase reveal the plasticity of CD4+ T cells and determine their range of dysfunctionalities within an otherwise sterile environment.