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Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection.
Snell, Laura M; Xu, Wenxi; Abd-Rabbo, Diala; Boukhaled, Giselle; Guo, Mengdi; Macleod, Bethany L; Elsaesser, Heidi J; Hezaveh, Kebria; Alsahafi, Nirmin; Lukhele, Sabelo; Nejat, Sara; Prabhakaran, Ramanandan; Epelman, Slava; McGaha, Tracy L; Brooks, David G.
Affiliation
  • Snell LM; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. lausnell@iu.edu.
  • Xu W; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. lausnell@iu.edu.
  • Abd-Rabbo D; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Boukhaled G; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Guo M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Macleod BL; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Elsaesser HJ; Department of Immunology, University of Toronto, Toronto, ON, Canada.
  • Hezaveh K; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Alsahafi N; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Lukhele S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Nejat S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Prabhakaran R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Epelman S; Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada.
  • McGaha TL; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Brooks DG; Department of Immunology, University of Toronto, Toronto, ON, Canada.
Nat Immunol ; 22(12): 1524-1537, 2021 12.
Article in En | MEDLINE | ID: mdl-34795443
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.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Lymphocyte Activation / Th1 Cells / B7-H1 Antigen / Immune Checkpoint Inhibitors / Lymphocytic Choriomeningitis / Lymphocytic choriomeningitis virus Limits: Animals Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2021 Type: Article Affiliation country: Canada

Full text: 1 Database: MEDLINE Main subject: Lymphocyte Activation / Th1 Cells / B7-H1 Antigen / Immune Checkpoint Inhibitors / Lymphocytic Choriomeningitis / Lymphocytic choriomeningitis virus Limits: Animals Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2021 Type: Article Affiliation country: Canada