Expression of novel long noncoding RNAs defines virus-specific effector and memory CD8+ T cells

William H Hudson,Donald J Mcguire,Julia Gensheimer,Nataliya Prokhnevska,Rafi Ahmed,Haydn T Kissick,Rama Akondy

doi:10.1038/s41467-018-07956-7

Abstract

In response to viral infection, CD8+ T cells undergo expansion and differentiate into distinct classes of effector cells. After clearance of the virus, a small population of long-lived memory cells persists. Comprehensive studies have defined the protein-coding transcriptional changes associated with this process. Here we expand on this prior work by performing RNA-sequencing to identify changes in long noncoding RNA (lncRNA) expression in human and mouse CD8+ T cells responding to viral infection. We identify hundreds of unannotated lncRNAs and show that expression profiles of both known and novel lncRNAs are sufficient to define naive, effector, and memory CD8+ T cell subsets, implying that they may be involved in fate decisions during antigen-driven differentiation. Additionally, in comparing mouse and human lncRNA expression, we find that lncRNAs with conserved sequence undergo similar changes in expression in the two species, suggesting an evolutionarily conserved role for lncRNAs during CD8+ T cell differentiation.

Highlights

In response to viral infection, CD8+ T cells undergo expansion and differentiate into distinct classes of effector cells
To construct the mouse CD8+ T cell transcriptome, we isolated virus-specific CD8+ T cell subsets from lymphocytic choriomeningitis virus (LCMV) infected mice: CD45.1+ LCMV-specific P14 CD8+ T cells were transferred to congenically distinct (CD45.2+) C57BL/6J recipient mice (Fig. 1a)
We developed an additional method of spliced transcript assembly to complement this approach, which we termed intron chain extension (ICE; see Methods, Supplementary Fig. 4)

Summary

Introduction

In response to viral infection, CD8+ T cells undergo expansion and differentiate into distinct classes of effector cells. Many of the same genetic programs observed in mice are conserved during effector and memory T cell differentiation in human subjects[4,5,6] While these previous studies provided extensive insight into the protein-coding changes associated with T cell differentiation, much less is known regarding expression of non-protein-coding transcripts during this process. We expand upon protein-focused transcriptional studies to identify the expression of known and novel lncRNAs in human and mouse virus-specific CD8+ T cell subsets. We find that human and mouse CD8+ T cell subsets can be defined by their proteincoding gene expression and by their expression patterns of known and novel lncRNA genes, implying similar regulation of transcription of protein-coding and noncoding transcripts. We identify several novel lncRNAs that are homologous, syntenous, and expressed in both species, suggesting an evolutionarily conserved role for these genes

Objectives

Methods

Results

Conclusion