Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease

• There are significant differences in time to peripheral blood T follicular helper cell recovery after hematopoietic cell transplantation, depending on donor source
• T follicular helper cell phenotypes after hematopoietic cell transplantation are similar between donor sources and do not differ in patients with or without chronic graft-versus-host disease
• Peripheral blood T follicular helper cells are significantly decreased in patients with chronic graft-versus-host disease

B cell antihost antibody production plays a central role in chronic graft-versus-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (versus matched related donors [MRD]) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17, and IL-21) after stimulation. In contrast to mouse models, where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells after both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.