RNA-seq of human T cells after hematopoietic stem cell transplantation identifies Linc00402 as a regulator of T cell alloimmunity

Daniel Peltier, Molly Radosevich, Visweswaran Ravikumar, Sethuramasundaram Pitchiaya, Thomas Decoville, Sherri C. Wood, Guoqing Hou, Cynthia Zajac, Katherine Oravecz-Wilson, David Sokol, Israel Henig, Julia Wu, Stephanie Kim, Austin Taylor, Hideaki Fujiwara, Yaping Sun, Arvind Rao, Arul M. Chinnaiyan, Daniel R. Goldstein, Pavan Reddy

Research output: Contribution to journalArticlepeer-review

Abstract

Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression was validated in an independent patient cohort and in mixed lymphocyte reactions using ex vivo healthy human T cells. We identified Linc00402, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. Linc00402 was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. Linc00402 was reduced in patients who subsequently developed acute graft-versus-host disease. Linc00402 enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and Egr-1 after T cell receptor engagement. Functionally, Linc00402 augmented the T cell proliferative response to an allogeneic stimulus but not to a nominal ovalbumin peptide antigen or polyclonal anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a regulator of allogeneic T cell function.

Original languageEnglish
Article numbereaaz0316
JournalScience Translational Medicine
Volume13
Issue number585
DOIs
Publication statusPublished - Mar 17 2021

ASJC Scopus subject areas

  • Medicine(all)

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