Suppressor T helper type 17 cell responses in intestinal transplant recipients with allograft rejection

Leonid Belyayev; Jiman Kang; Mohammed Sadat; Katrina Loh; Digvijay Patil; Vinona Muralidaran; Khalid Khan; Stuart Kaufman; Sukanya Subramanian; Yuriy Gusev; Krithika Bhuvaneshwar; Habtom Ressom; Rency Varghese; Udeme Ekong; Cal S Matsumoto; Simon C Robson; Thomas M Fishbein; Alexander Kroemer

doi:10.1016/j.humimm.2024.110773

Suppressor T helper type 17 cell responses in intestinal transplant recipients with allograft rejection

Hum Immunol. 2024 Mar 16:110773. doi: 10.1016/j.humimm.2024.110773. Online ahead of print.

Authors

Leonid Belyayev¹, Jiman Kang², Mohammed Sadat³, Katrina Loh³, Digvijay Patil³, Vinona Muralidaran³, Khalid Khan³, Stuart Kaufman³, Sukanya Subramanian³, Yuriy Gusev⁴, Krithika Bhuvaneshwar⁴, Habtom Ressom⁵, Rency Varghese⁵, Udeme Ekong³, Cal S Matsumoto³, Simon C Robson⁶, Thomas M Fishbein³, Alexander Kroemer⁷

Affiliations

¹ MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007, USA; Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20814, USA.
² MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007, USA; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20007, USA.
³ MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007, USA.
⁴ Innovation Center for Biomedical Informatics (ICBI), Georgetown University Medical Center, 2115 Wisconsin Ave NW, Suite 110, Washington, DC 20075, USA.
⁵ Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20008, USA.
⁶ Center for Inflammation Research, Department of Anesthesiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA.
⁷ MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007, USA. Electronic address: alexander.kroemer@gunet.georgetown.edu.

PMID: 38494386
DOI: 10.1016/j.humimm.2024.110773

Abstract

Background: Intestinal transplant (ITx) rejection is associated with memory T helper type 17 cell (Th17) infiltration of grafted tissues. Modulation of Th17 effector cell response is facilitated by T regulatory (Treg) cells, but a phenotypic characterization of this process is lacking in the context of allograft rejection.

Methods: Flow cytometry was performed to examine the expression of surface receptors, cytokines, and transcription factors in Th17 and Treg cells in ITx control (n = 34) and rejection patients (n = 23). To elucidate key pathways guiding the rejection biology, we utilized RNA sequencing (RNAseq) and assessed epigenetic stability through pyrosequencing of the Treg-specific demethylated region (TSDR).

Results: We found that intestinal allograft rejection is characterized by Treg cellular infiltrates, which are polarized toward Th17-type chemokine receptor, ROR-γt transcription factor expression, and cytokine production. These Treg cell subsets have maintained epigenetic stability, as defined by FoxP3-TSDR methylation status, but displayed upregulation of functional Treg and purinergic signaling genes by RNAseq analysis such as CD39, in keeping with suppressor Th17 properties.

Conclusion: We show that ITx rejection is associated with increased polarized cells that express a Th17-like phenotype concurrent with regulatory purinergic markers.

Keywords: FoxP3; Intestinal transplantation; Th17; Treg.