Beta-2 adrenergic receptor in CD8+ T cells inhibits GVHD through transcriptional modulation of differentiation and exhaustion.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for selected hematologic diseases. However, graft-versus-host disease (GVHD) limits broader application of allo-HCT. The catecholaminergic sympathetic nervous system modulates immune cells. Beta-2 adrenergic Receptor (β2AR) acts as an immune checkpoint, yet its role in CD8+ T cells remains poorly understood. We used an MHC-mismatched model of acute GVHD to study how β2AR activity on donor CD8+ T cells affects GVHD severity. Host mice receiving β2AR+/+ (WT) CD8+ T cells demonstrated less severe GVHD, lower inflammatory cytokines in peripheral circulation, decreased donor CD8+ T cell expansion, and reduced central memory formation compared to host mice receiving β2AR-/- (KO) CD8+ T cells. Single cell RNA-seq and flow cytometry analyses revealed that donor-derived KO CD8+ T cells had an increased Tc1/Tc17 signature (T-Bet, IFNγ, TNFα, RORγT, and IL23r), expressed lower levels of Eomes and Gata3, and expressed inhibitory PD1, Tim3, Lag3, and CTLA4 less frequently than β2AR WT counterparts. In addition, host mice receiving KO CD8+ T cells exhibit a stronger graft-versus-lymphoma effect than host mice receiving β2AR WT CD8+ T cells. Together, these results indicate that β2AR activity in donor CD8+ T cells inhibits GVHD through transcriptional modulation of T cell differentiation and exhaustion, including a T-Bet/Eomes and PD1 relevant process.