PD-1 checkpoint blockade activates germinal center follicular T cell programs that disrupt type 2 isotype-specific antibody homeostasis

Abstract

ABSTRACTMultiple CD4 T cell dependent tolerance mechanisms control adaptive B cell immunity to environmental antigens. We recently demonstrated a PD-1 checkpoint within steady-state splenic germinal centers (GC) that constrains the maturation of type 2 IgG1 isotype-specific antibody homeostasis. Here, we utilized single cell-indexed custom RNA-sequencing to probe the follicular T cell mechanisms directly targeted by acute PD-1 blockade. We find a pre-existing subset of follicular helper T (TFH) cells that express type 2 immune response properties (TFH2) with exaggerated pathways of TCR activation, cytokine signaling, and enhanced cell-cell contact upon acute PD-1 blockade. This selective amplification of the TFH2 program significantly increases predicted molecular connections to type 2 IgG1 GC B cells that dominate limited changes in GC localized follicular regulatory T (GC TFR) cell programs. These studies demonstrate how type 2 isotype-specific adaptive B cell tolerance is selectively disrupted by acute PD-1 blockade to reveal the modular regulatory mechanisms that control splenic GC dynamics at homeostasis.One Sentence SummaryAcute PD-1 blockade alters the regulatory dynamic of the steady state germinal center to drive the maturation of IgG1 GC B cells towards PC differentiation in a process mediated by type 2 like TFH effector molecules.HIGHLIGHTS-Acute PD-1 blockade enhances the steady state splenic TFH program-PD-1 blockade selectively exaggerates a Type 2 like TFH module-GC TFR cells are minimally impacted by blockade-PD-1 restrains predicted TFH2 functional contacts with IgG1 GC B Cells