Highlights d Th1 functionalities are reduced by persisting antigen in doseand time-dependent manner d Signaling pathways are adjusted to persisting antigen with different sensitivities d Gene transcription is dynamically and reversibly adjusted to persisting antigen d About half of the genes affected by antigen persistence respond in a dose-specific manner
CD8 + T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine + (PS) extracellular vesicles (EVs). These EVs interact especially with CD8 + T cells; however, it remains unclear whether they can actively modulate CD8 + T cell responses. In this study, we have developed a method to analyze cell-bound PS + EVs and their target cells in vivo. We show that EV + cell abundance increases during viral infection and that EVs preferentially bind to activated, but not naive, CD8 + T cells. Superresolution imaging revealed that PS + EVs attach to clusters of CD8 molecules on the T cell surface. Furthermore, EV-binding induces antigen (Ag)-specific TCR signaling and increased nuclear translocation of the transcription factor Nuclear factor of activated T-cells (NFATc1) in vivo. EV-decorated but not EV-free CD8 + T cells are enriched for gene signatures associated with T-cell receptor signaling, early effector differentiation, and proliferation. Our data thus demonstrate that PS + EVs provide Ag-specific adjuvant effects to activated CD8 + T cells in vivo.
Exhausted immune responses to chronic diseases represent a major challenge to global health. To explore their cell fate and plasticity in exhaustion, we analyzed CD4+T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase, and are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion markers, resemble naturally anergic cells and become unable to help B cells and, at the highest dose, undergo apoptosis. Mechanistically, TCR signaling pathways are modulated with increasing dose and time. Ca2+ fluxes were found to be more robust to persistent antigen presentation while the MAPK and Akt pathways are easily desensitized. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Preliminary data indicate that antigen-exhausted CD4+T cells retain their plasticity for at least 30 days and are able to adjust to different levels of antigen. Our data suggest a dynamic response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.
Exhausted immune responses to chronic diseases represent a major challenge to global health. We studied CD4+ T cells in a mouse model where presentation of their antigen can be regulated. When the cells are driven through the effector phase, but are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion and anergy markers, modulate their MAP kinase, mTORC1 and Ca2+/calcineurin signaling pathways with dose and time, lose their capacity to transmit help to B cells and undergo, at the highest dose, apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. The cells also adapt to antigen removal and recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.
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