Eosinophils Restrain Humoral Alloimmunity after Lung Transplantation [scRNA-seq]

While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils’ role in alloimmunity based on context and organ type. Due to their prevalence in the lung, and their defined role in other pulmonary pathology such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody secreting cell differentiation and resulted in de novo-generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4+Foxp3-Bcl6+CXCR5+PD1+ T follicular helper cells (Tfh) which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naïve CD4+ T cells. Our data thus describe a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggests that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.