Using an adoptive CD4+ T cell transfer mouse model of chronic LCMV infection, Snell et al. showed that anti-PD-L1 therapy selectively impacted cycling cells to increase virus-specific CD4+ TH1 cells. TFH cells were diverted, and pre-committed TH1 cells were pushed to differentiate to TH1 lineage cells enriched for expression of Foxp3 and TH1-associated inhibitory and activation markers. Anti-PD-L1 treatment increased Treg infiltration and directly amplified TH1-like Tregs in the spleen, lungs, and liver. Gene expression analyses showed that anti-PD-L1 decreased TCR signaling, recasted IFN-I to IFNγ responses, and restored CD4+ T cell cytolytic capacity.
Contributed by Paula Hochman
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 (T(H)) cell responses or the ability to restore CD4(+) T(H)-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4(+) T(H)1 cell amplification, prevents CD4(+) T(H)1 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 T(H)1-like T regulatory cells, demonstrating a system-wide CD4-T(H)1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-_-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.
Author Info: (1) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. lausnell@iu.edu. Department of Microbiology and Immunology, Indiana University School of Medici
Author Info: (1) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. lausnell@iu.edu. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. lausnell@iu.edu. (2) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (3) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (4) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (5) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Department of Immunology, University of Toronto, Toronto, ON, Canada. (6) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (7) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (8) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (9) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (10) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (11) Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada. (12) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (13) Department of Immunology, University of Toronto, Toronto, ON, Canada. Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada. Peter Munk Cardiac Centre, Ted Rogers Centre for Heart Research, Toronto, ON, Canada. (14) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Department of Immunology, University of Toronto, Toronto, ON, Canada. (15) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. dbrooks@uhnresearch.ca. Department of Immunology, University of Toronto, Toronto, ON, Canada. dbrooks@uhnresearch.ca.
