Regulation of T follicular helper cells in the germinal center reaction of chronic graft-versus-host disease

Abstract

Chronic graft-versus-host disease (GVHD) is a major complication following allogeneic hematopoietic stem cell transplantation, leading to significant long-term morbidity, mortality, and diminished quality of life. Though improvements in transplantation practices have led to the reduction in the incidence of acute GVHD, the occurrence of chronic GVHD remains unaffected, and additional therapeutic approaches must be investigated to address this unique pathophysiology. The germinal center reaction that produces pathogenic immunoglobulin is a significant contributor to chronic GVHD pathology and we therefore look to regulate the factors that support versus suppress the germinal center reaction in order to treat chronic GVHD. In this work, we explore the modulation of metabolic and co-inhibitory pathways to achieve this end.Our studies identify a temporal shift in the metabolic pathways used by the T follicular helper cells that support germinal center B cell activity, from initial dependence on glycolysis to later substantial utilization of mitochondrial respiration. This discovery informs future immunometabolic methods to control the germinal center response and validates the use of pharmaceutical agents inhibiting mitochondrial pyruvate transport for the alleviation of chronic GVHD. Our studies also establish PD-1 pathway support for the germinal center reaction, and identify the ITIM, but not ITSM, PD-1 signaling motif as necessary for T follicular helper cell function in assisting B cell-mediated immune responses. We also find that blockade of the PD-1 axis through monoclonal antibody administration or nonfunctional mutation in ITIM results in T follicular helper cells adopting suppressive T follicular regulatory cell characteristics, and leads to the attenuation of chronic GVHD. Collectively, this research provides new insights into the biology of the germinal center reaction that enables T cell-dependent humoral immunity and identifies new potential therapeutic means for the treatment of chronic GVHD.