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. 2021 Dec;22(12):1524-1537.
doi: 10.1038/s41590-021-01060-7. Epub 2021 Nov 18.

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

Laura M Snell  1   2 , Wenxi Xu  3 , Diala Abd-Rabbo  3 , Giselle Boukhaled  3 , Mengdi Guo  3   4 , Bethany L Macleod  3 , Heidi J Elsaesser  3 , Kebria Hezaveh  3 , Nirmin Alsahafi  3 , Sabelo Lukhele  3 , Sara Nejat  5 , Ramanandan Prabhakaran  3 , Slava Epelman  4   5   6 , Tracy L McGaha  3   4 , David G Brooks  7   8
Affiliations

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

Laura M Snell et al. Nat Immunol. 2021 Dec.

Abstract

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.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Extended Data Fig. 1 |
Extended Data Fig. 1 |. CyTOF gating scheme.
Extended Data Fig. 2 |
Extended Data Fig. 2 |. Enhancement of virus-specific CD4+ TH1 cells by PD-L1 blockade occurs prior to decreased virus titers.
Extended Data Fig. 3 |
Extended Data Fig. 3 |. Pre-therapy cycling CD4+ SMARTA T cell populations are targets of anti-PD-L1 blockade.
Extended Data Fig. 4 |
Extended Data Fig. 4 |. PD-L1 blockade targets cycling, TH1-phenotype Treg cells.
Extended Data Fig. 5 |
Extended Data Fig. 5 |. Single cell transcriptomic analyses of virus-specific CD4+ T cells following PD-L1 blockade.
Extended Data Fig. 6 |
Extended Data Fig. 6 |. Pathway analysis of CD4+ SMARTA T cells following PD-L1 blockade.
Extended Data Fig. 7 |
Extended Data Fig. 7 |. Cytotoxic gene expression in all SMARTA clusters from single cell analysis.
Extended Data Fig. 8 |
Extended Data Fig. 8 |. Flow gating scheme for sorting.
Fig. 1 |
Fig. 1 |. PD-L1 blockade specifically amplifies and functionally enhances CD4+ TH1 cells.
Fig. 2 |
Fig. 2 |. Pretherapy cycling CD4+ SMARTA T cells are expanded upon PD-L1 blockade.
Fig. 3 |
Fig. 3 |. PD-L1 blockade specifically expands and activates TH1-like Treg cells.
Fig. 4 |
Fig. 4 |. PD-L1 blockade expands and induces tissue infiltration of Treg cells in nonlymphoid organs.
Fig. 5 |
Fig. 5 |. PD-L1 blockade enhances TH1 gene programs and terminal differentiation of TH1 cells.
Fig. 6 |
Fig. 6 |. PD-L1 blockade reorients intracellular interferon and TCR signaling.
Fig. 7 |
Fig. 7 |. PD-L1 blockade restores virus-specific CD4+ CTL function.
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References

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