Exercise augments the ex vivo expansion of viral-specific T-cells for adoptive transfer immunotherapy via β2-adrenergic receptor signaling

Abstract

The adoptive transfer of viral-specific T-cells (VSTs) is highly effective in treating viral infections after allogeneic hematopoietic stem cell transplant. Unfortunately, adoptive T-cell therapy is not available for a large number of patients due to logistical constraints associated with isolating and manufacturing enough VSTs from healthy donors. We have shown that a single exercise bout reliably augments the ex vivoexpansion of VSTs and thus might be useful as a clinical adjuvant to boost the manufacture of VSTs from healthy donors. We sought to determine if the augmenting effects of exercise on VST expansion are dependent on β2 adrenergic receptor (β2AR) signaling. Using a randomized cross-over and double-blinded design, ten subjects performed 30-min of steady state cycling exercise 3 h after ingesting (i) a placebo, (ii) a β1 + 2AR antagonist (nadolol), or (iii) a β1AR antagonist (bisoprolol). PBMCs isolated before and after exercise were stimulated with Adenovirus (AdV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) peptide antigens and cultured for 8 days, after which VSTs were enumerated by IFNγ ELISPOT. Compared to resting conditions, exercise augmented the expansion of VSTs in the placebo and bisoprolol trials (38.2% and 57.9% increases), but not in the nadolol trial (3.3% decrease). We conclude that the augmenting effects of exercise on VST expansion are dependent on β2AR signaling, highlighting the β2AR as a potential target to increase the potency of T-cell therapeutics.