Tissue-specific Regulatory T Cells: Biomarker for Acute Graft-vs-host Disease and Survival

Regulatory T cells (Tregs) are a subset of CD4(+) T cells that are characterized by the expression of CD25 and Foxp3 and are capable of suppressing alloimmune responses. We assessed whether high frequencies of circulating skin or gut tissue-specific Tregs at engraftment could predict acute graft-vs-host disease (aGVHD) incidence and survival in a cohort of hematopoietic cell transplant (HCT) recipients. Tregs were analyzed at engraftment in 74 patients receiving HCT. Treg skin-homing (CLA(+)) or gut-homing (α(4)β(7)(+)) subsets were identified by flow cytometry, and patients were divided into high CLA(+) Tregs or high α(4)β(7)(+) Tregs groups, using the 75(th) percentile of tissue-specific Treg percentages as a threshold. At day +100 post-HCT, the cumulative incidence of any stage skin or gut aGVHD was significantly lower in those patients with high CLA(+) Tregs or high α(4)β(7)(+) Tregs at engraftment, respectively (high CLA(+) Tregs, 24.0% vs low CLA(+) Tregs, 55.1%; p = 0.011 for skin aGVHD or high α(4)β(7)(+) Tregs, 47.3% vs low α(4)β(7)(+) Tregs, 74.5%; p = 0.029 for gut aGVHD). The 2-year probabilities of overall survival and nonrelapse mortality were 73.4% and 7.5% among patients with high frequencies of tissue-specific Tregs vs 49.4% and 36.1% for those with both low CLA(+) Tregs and low α(4)β(7)(+) Tregs (p = 0.039, p = 0.010). These results suggest that a threshold value for CLA(+) or α(4)β(7)(+) Tregs could be used to predict important HCT outcomes, and to direct the rationale use of tissue-specific pre-emptive therapies to decrease clinical aGVHD and improve HCT survival.