Modulation of tissue resident memory T cells by glucocorticoids after acute cellular rejection in lung transplantation

Author:

Snyder Mark E.123ORCID,Moghbeli Kaveh1ORCID,Bondonese Anna1ORCID,Craig Andrew1ORCID,Popescu Iulia1ORCID,Fan Li1ORCID,Tabib Tracy1ORCID,Lafyatis Robert1ORCID,Chen Kong1ORCID,Trejo Bittar Humberto E.4ORCID,Lendermon Elizabeth1ORCID,Pilewski Joseph1ORCID,Johnson Bruce1ORCID,Kilaru Silpa1ORCID,Zhang Yingze1ORCID,Sanchez Pablo G.5ORCID,Alder Jonathan K.1ORCID,Sims Peter A.6ORCID,McDyer John F.13ORCID

Affiliation:

1. Department of Medicine, University of Pittsburgh, Pittsburgh, PA 1

2. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 2

3. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 5

4. Department of Pathology, University of Pittsburgh, Pittsburgh, PA 3

5. Department of Surgery, University of Pittsburgh, Pittsburgh, PA 4

6. Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 6

Abstract

Acute cellular rejection is common after lung transplantation and is associated with an increased risk of early chronic rejection. We present combined single-cell RNA and TCR sequencing on recipient-derived T cells obtained from the bronchoalveolar lavage of three lung transplant recipients with rejection and compare them with T cells obtained from the same patients after treatment of rejection with high-dose systemic glucocorticoids. At the time of rejection, we found an oligoclonal expansion of cytotoxic CD8+ T cells that all persisted as tissue resident memory T cells after successful treatment. Persisting CD8+ allograft-resident T cells have reduced gene expression for cytotoxic mediators after therapy with glucocorticoids but accumulate around airways. This clonal expansion is discordant with circulating T cell clonal expansion at the time of rejection, suggesting in situ expansion. We thus highlight the accumulation of cytotoxic, recipient-derived tissue resident memory T cells within the lung allograft that persist despite the administration of high-dose systemic glucocorticoids. The long-term clinical consequences of this persistence have yet to be characterized.

Funder

National Institutes of Health

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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