The Role of the T Regulatory Cell Compartment in Intestinal Transplant Patients: Helpful or Unhinged?

L. Belyayev¹, M. Sadat², K. Loh³, S. Moturi², K. Khan², J. Hawksworth², C. Matsumoto², T. M. Fishbein², A. Kroemer²

¹Surgery, Walter Reed National Military Medical Center, Bethesda, MD, ²Transplant, MedStar Georgetown Transplant Institute, Washington D.C., DC, ³Pediatrics, Children’s National Medical Center, Washington D.C., DC

Meeting: 2019 American Transplant Congress

Abstract number: 516

Keywords: Inflammation, Intestinal transplantation, Rejection, T helper cells

Session Information

Session Name: Concurrent Session: Small Bowel

Session Type: Concurrent Session

Date: Tuesday, June 4, 2019

Session Time: 2:30pm-4:00pm

Presentation Time: 2:42pm-2:54pm

Location: Room 209

*Purpose: The T regulatory (Treg) cell compartment has now been established as a key player in dampening T helper 17 (Th17) mediated inflammation, managing self-tolerance, and preventing autoimmunity in a milieu of autoimmune conditions and intestinal transplantation (ITx) where a need exists for a full tissue phenotypic and functional characterization of the Treg/Th17 axis; We hypothesized that the Treg/Th17 cell axis in ITx rejection is dysbalanced towards unrestricted Th17-mediated inflammation in the allograft.

*Methods: We identified a cohort of ITx patients with a history of rejection along with uncomplicated controls from our IRB-approved Immunomonitoring and Tissue Bank Study. A polychromatic flow cytometry (PFC) panel with and without PMA stimulation and culture was used to analyze peripheral blood and intestinal allograft samples to characterize surface receptor phenotype, transcription factor expression, and cytokine production.

*Results: PFC of biopsies showed a significant increase in CCR6+ IL-17 producing Th17 effector cells in rejection patients as compared to controls. To our surprise there was an overall increase in the proportion of CD25+ FoxP3+ Tregs in rejection patients however the majority of which were induced (Helios-) with less natural thymic derived Tregs (Helios+) which was not appreciated in blood PFC. Further Treg subset analysis revealed a significantly higher proportion of Th17-like CCR6 expressing and Th1/Th17-like dual CXCR3/CCR6 expressing memory (CCR4+CD45RA-) Tregs in rejection patients. Therefore we hypothesized that given Treg plasticity in a pro-inflammatory environment these Th17-like Tregs in ITx rejection assume an effector like phenotype. To test this hypothesis we performed an ex vivo restimulation assay which demonstrated that both natural and induced Tregs produce more IL-17 in rejection than control patients further corroborating their pro-inflammatory phenotype and disbalance in the Th17/Treg axis.

*Conclusions: Our study characterizes ITx rejection as driven by a severely altered Treg/Th17 axis with IL-17 producing CCR6+ Th17 effector and potentially pro-inflammatory Treg cells which may have strong implications on future clinical therapies.

To cite this abstract in AMA style:

Belyayev L, Sadat M, Loh K, Moturi S, Khan K, Hawksworth J, Matsumoto C, Fishbein TM, Kroemer A. The Role of the T Regulatory Cell Compartment in Intestinal Transplant Patients: Helpful or Unhinged? [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/the-role-of-the-t-regulatory-cell-compartment-in-intestinal-transplant-patients-helpful-or-unhinged/. Accessed November 25, 2024.

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