Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection

Autor: Bethany L. MacLeod, W. Xu, Giselle Boukhaled, Sabelo Lukhele, Diala Abd-Rabbo, Mengdi Guo, Laura M. Snell, Sara Nejat, Heidi Elsaesser, Tracy L. McGaha, Slava Epelman, Kebria Hezaveh, David G. Brooks, Ramanandan Prabhakaran, Nirmin Alsahafi
Rok vydání: 2021
Předmět:
Zdroj: Nature Immunology. 22:1524-1537
ISSN: 1529-2916
1529-2908
DOI: 10.1038/s41590-021-01060-7
Popis: Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4–TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration. Snell et al. examine the heterogeneity of CD4+ T cells in chronic viral infection, showing that PD-L1 blockade enhances a cytotoxic gene program in antigen-specific TH1 cells and can restore antiviral CD4+ T cell killer function.
Databáze: OpenAIRE
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