Impact of Induction Therapy on Circulating T Follicular Helper Cells and Subsequent Donor-Specific Antibody Formation After Kidney Transplant

Introduction: The cellular events that contribute to generation of donor-specific anti-HLA antibodies (DSA) post-kidney transplantation (KTx) are not well understood. Characterization of such mechanisms could allow tailoring of immunosuppression to benefit sensitized patients. Methods: We prospectively monitored circulating T follicular helper (cT _FH ) cells in KTx recipients who received T-cell depleting (thymoglobulin, n = 54) or T-cell nondepleting (basiliximab, n = 20) induction therapy from pre-KTx to 1 year post-KTx and assessed their phenotypic changes due to induction and DSA occurrence, in addition to healthy controls (n = 13), for a total of 307 blood samples. Results: Before KTx, patients displayed comparable levels of resting, central memory cT _FH cells with similar polarization to those of healthy controls. Unlike basiliximab induction, thymoglobulin induction significantly depleted cT _FH cells, triggered lymphopenia-induced proliferation that skewed cT _FH cells toward increased Th1 polarization, effector memory, and elevated programmed cell death protein 1 (PD-1) ^int/hi expression, resembling activated phenotypes. Regardless of induction, patients who developed DSA post-KTx, harbored pre-KTx donor-reactive memory interleukin (IL)-21 ⁺ cT _FH cells and showed higher % cT _FH and lower % of T regulatory (T _REG ) cells post-KTx resulting in elevated cT _FH :T _REG ratio at DSA occurrence. Conclusion: Induction therapy distinctly shapes cT _FH cell phenotype post-KTx. Monitoring cT _FH cells before and after KTx may help detect those patients prone to DSA generation post-KTx.