A long noncoding RNA whose function was previously unknown turns out to play a vital role in mobilizing the immune response following a bone marrow transplant or solid organ transplantation, according to researchers at the University of Michigan (U-M) Rogel Cancer Center and Michigan Medicine. This RNA molecule, cataloged in scientific databases simply as Linc00402, helps activate T cells in response to the presence of foreign human cells.
The findings of the team’s study “RNA-seq of human T cells after hematopoietic stem cell transplantation identifies Linc00402 as a regulator of T cell alloimmunity,” published in Science Translational Medicine, suggest that inhibiting the RNA therapeutically might improve outcomes for transplant recipients.
“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,” write the investigators.
“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.”
“We see a lot of graft-versus-host disease, or GVHD, which is a potentially fatal complication that can happen after transplant when T cells in the donor’s blood see the transplant recipient’s cells as invaders and attack them,” says lead author Daniel Peltier, MD, PhD, a pediatric bone marrow transplant physician at U-M. “Unfortunately, the medicines we use to prevent GVHD suppress the immune system and can raise the risk of a cancer relapse or infection, and they also have other side effects,” adding that he and his colleagues have worked on finding a way of targeting just the problematic components of the immune system that cause GVHD.
One reason for looking at this particular type of RNA molecule is that they tend to be expressed only by a limited number of tissues in a limited number of contexts, explains senior study author Pavan Reddy, MD, deputy director of the Rogel Cancer Center and division chief of hematology/oncology at Michigan Medicine.
“So, unlike a lot of RNAs, which are expressed in all kinds of cells by all kinds of living things, long noncoding RNAs offer the possibility that we might be able to target them in a relatively unique and disease-specific way,” he explains.
If doctors can find a way to zero-in and short circuit just the T cells’ tendency to get aggressive in response to the transplant, they may not need to suppress the patient’s immune system in a more general way that leaves them susceptible to infection or a regrowth of their cancer.
The researchers are hopeful the discoveries could also be used to help predict which patients are most likely to develop GVHD.
As new details about Linc00402 come to light, the researchers are also proposing giving the RNA a more memorable name. In the study, they propose calling it ReLot, for regulatory long noncoding RNA of T cells.
“Scientists have only relatively recently started decoding the importance of some of these parts of the genome that don’t code for proteins,” Peltier says. “It’s really only been since the robust sequencing of the transcriptome that we realized that the 80–90% that we thought was ‘junk DNA’ is definitely not junk.”
