Activated Circulating Memory T Follicular Helper Cells with Self-Renewal Potential Underlie the Kidney Allograft Antibody-Mediated Rejection Response

Activated Circulating Memory TFollicular Helper Cells with Self-Renewal Potential Underlie the Kidney Allograft Antibody-Mediated Rejection Response

K. Louis¹, C. Macedo¹, E. Bailly¹, B. Ramaswami¹, M. Marrari¹, T. Shi¹, D. Landsittel¹, U. Chandran¹, P. Fadakar¹, M. Yamada¹, G. Chalasani¹, P. Randhawa¹, A. Zeevi¹, C. Lefaucheur², D. Metes¹

¹Surgery, University of Pittsburgh, Pittsburgh, PA, ²Inserm UMR 976, Paris, France

Meeting: 2020 American Transplant Congress

Abstract number: 613

Keywords: Alloantibodies, Kidney, Rejection, T helper cells

Session Information

Session Name: Lymphocyte Biology: Signaling, Co-Stimulation, Regulation

Session Type: Oral Abstract Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:45pm

Presentation Time: 3:51pm-4:03pm

Location: Virtual

*Purpose: Antibody-mediated rejection (ABMR) is the leading cause of allograft failure after organ transplantation. Yet, the cellular events that lead to the induction of a deleterious donor-specific antibody (DSA) response remain poorly understood.

*Methods: Using high-dimensional flow cytometry, in vitro assays and RNA-sequencing, we investigated the phenotype, function and transcriptome of memory T- and B-cells from 105 kidney transplant recipients consisting of : patients who did not develop DSA nor ABMR (N=54), patients who developed DSA without ABMR (N=31) and patients with DSA accompanied by ABMR (N=20) in the first 24 months post-transplant.

*Results: We have identified an expanded population of memory CD4⁺CD45RO+CXCR5⁺ cells in blood of patients with ABMR that was actively proliferating. These circulating T follicular helper cells (cT_FH) upregulated the activation markers ICOS and PD-1 (P<0.001 and P=0.02), displayed a CCR7⁺CD127⁺ memory precursor phenotype and were significantly enriched for the critical transcriptional regulators of early T_FH differentiation and function TCF7, LEF1 and MAF (P<0.001 for all). In contrast, in the absence of DSA or ABMR development, cT_FH were largely quiescent, non-proliferating with an effector memory differentiation. Consistently, cT_FH from patients with ABMR produced large amounts of IL-21 (P=0.01) upon alloantigen stimulation and were highly functional at inducing memory B cells to differentiate into DSA-secreting cells in vitro. This sustained B-cell help was also manifested in vivo by the emergence of proliferating memory B cells and antibody-secreting cells (P<0.001 for both) and the release of CXCL13 (P=0.002). The increased generation of DSAs of multiple isotypes including IgG3 (P=0.03), further indicated efficient memory cT_FH-B cell interactions and germinal center activity during ABMR. Additionally, patients with ABMR and high accumulation of blood Ki67⁺ICOS⁺ cT_FH displayed more severe allograft rejection lesions and higher rate of allograft loss (P=0.0013).

*Conclusions: Thus, patients undergoing ABMR may potentially benefit from specific treatments targeting T_FH cells.

To cite this abstract in AMA style:

Louis K, Macedo C, Bailly E, Ramaswami B, Marrari M, Shi T, Landsittel D, Chandran U, Fadakar P, Yamada M, Chalasani G, Randhawa P, Zeevi A, Lefaucheur C, Metes D. Activated Circulating Memory TFollicular Helper Cells with Self-Renewal Potential Underlie the Kidney Allograft Antibody-Mediated Rejection Response [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/activated-circulating-memory-t-follicular-helper-cells-with-self-renewal-potential-underlie-the-kidney-allograft-antibody-mediated-rejection-response/. Accessed November 22, 2024.

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