Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 13, Issue 585, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaz0316
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Funding
- NIH T32 Training Grant in Molecular and Translational Hematology [4T32HL007622-30]
- NIH K12 Children's Health Research Center Development Award [5K12HD028820-27]
- Hope from Harper St. Baldrick's Foundation Fellowship
- Hyundai Hope on Wheels Young Investigator Grant
- NIH RO1 [HL128046, CA203542, CA217156]
- NCI-SPORE Career Enhancement Award
- PCF Young Investigator Award
- Department of Defense Idea Development Award
- NIH [UL1TR002240, R01-AI138347]
- American Cancer Society [RSG-16-005-01]
- CCSG [P30 CA046592]
- University of Michigan
- NCI [R37CA214955-01A1]
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This study identified Linc00402 as a significant regulator of allogeneic T cell function, enhancing proliferative response to allogeneic stimuli by increasing ERK1 and ERK2 activity, FOS nuclear accumulation, and expression of interleukin-2 and Egr-1. Additionally, Linc00402 was decreased in patients who developed acute graft-versus-host disease after transplantation.
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.
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