Alterations in Peripheral Blood Follicular Helper T Cell (TFH) Subsets and TREG in Kidney Transplant Recipients With DSA.

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Donor-specific anti-HLA antibodies (DSA) represent a key risk factor for acute and chronic rejection, and are a major cause of long-term graft failure after kidney transplantation (KTx). The immunological mechanisms that lead to the development of DSA are not entirely understood. We postulated that an imbalance between TFH (CD4+CD45RO+CXCR5+), which provide key help for antibody production by B cells, and TREG (CD4+CD25highFoxP3+CD127-) correlates with the development of DSA after Tx. Twenty-six thymoglobulin-induced KTx patients participating in an ongoing prospective study were monitored for DSA occurrence in the first year after Tx. During this period, 7 patients were identified as DSA positive by Luminex Single Antigen Bead Assay (cut-off 1000 MFI). Three patients developed DSA by day 30 post-Tx, while 3 presented DSA after day 180. Moreover, one patient had DSA pre-Tx that showed a 4 fold increase by day 30 post-Tx. In addition, 6 healthy control (HC) subjects and 5 DSA negative KTx recipients were included as controls. Whole blood was obtained at regular intervals before and after Tx, and analyzed by flow cytometry.We observed that the overall frequency of circulating TFH cells was not significantly different among the three groups: KTx recipients with DSA, KTx recipients with no DSA, and HC. However, the % of circulating Th1-TFH (CD4+CD45RO+CXCR3+CXCR5+) cells was significantly increased and the % of circulating TREG was decreased in KTx patients with DSA, as compared to their own pre-Tx values and to HC, resulting in a significantly increased Th1-TFH:TREG ratio. In addition, KTx patients with no DSA displayed comparable levels of Th1-TFH and TREG to those of HC, but significantly lower % of Th1-TFH compared to DSA positive patients.In conclusion, patients who develop DSA display a significant skewing of TFH cell subsets toward a Th1-TFH phenotype, accompanied by a concomitant decrease in TREG that results in elevated Th1-TFH:TREG ratio. This finding suggests that an altered balance of TFH cell subsets and TREG is associated with DSA generation after KTx.