Journal
SCIENCE IMMUNOLOGY
Volume 3, Issue 19, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aan8664
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Funding
- NIH [U19AI118626, U19AI118610, R01HL114093, R24AI108564, HHSN272200900042C, HHSN27220140045C]
- William K. Bowes Jr. Foundation
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027366] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL114093] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI118626, U19AI118610, R24AI108564, P01AI106695] Funding Source: NIH RePORTER
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CD4(+) cytotoxic T lymphocytes (CD4-CTLs) have been reported to play a protective role in several viral infections. However, little is known in humans about the biology of CD4-CTL generation, their functional properties, and heterogeneity, especially in relation to other well-described CD4(+) memory T cell subsets. We performed single-cell RNA sequencing in more than 9000 cells to unravel CD4-CTL heterogeneity, transcriptional profile, and clonality in humans. Single-cell differential gene expression analysis revealed a spectrum of known transcripts, including several linked to cytotoxic and costimulatory function that are expressed at higher levels in the T-EMRA (effector memory T cells expressing CD45RA) subset, which is highly enriched for CD4-CTLs, compared with CD4(+) T cells in the central memory (T-CM) and effector memory (T-EM) subsets. Simultaneous T cell antigen receptor (TCR) analysis in single cells and bulk subsets revealed that CD4-T-EMRA cells show marked clonal expansion compared with T-CM and T-EM cells and that most of CD4-T-EMRA were dengue virus (DENV)-specific in donors with previous DENV infection. The profile of CD4-T-EMRA was highly heterogeneous across donors, with four distinct clusters identified by the single-cell analysis. We identified distinct clusters of CD4-CTL effector and precursor cells in the T-EMRA subset; the precursor cells shared TCR clonotypes with CD4-CTL effectors and were distinguished by high expression of the interleukin-7 receptor. Our identification of a CD4-CTL precursor population may allow further investigation of how CD4-CTLs arise in humans and, thus, could provide insights into the mechanisms that may be used to generate durable and effective CD4-CTL immunity.
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