RNA-seq of human T cells after hematopoietic stem cell transplantation identifies <i>Linc00402</i> as a regulator of T cell alloimmunity.

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 <i>Linc00402</i>, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that <i>Linc00402</i> was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. <i>Linc00402</i> was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. <i>Linc00402</i> was reduced in patients who subsequently developed acute graft-versus-host disease. <i>Linc00402</i> enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and <i>Egr-1</i> after T cell receptor engagement. Functionally, <i>Linc00402</i> 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 <i>Linc00402</i> as a regulator of allogeneic T cell function.