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Research Article

Proliferation-competent Tcf1+ CD8 T cells in dysfunctional populations are CD4 T cell help independent

View ORCID ProfileKristiyan Kanev, Ming Wu, Antar Drews, Patrick Roelli, Christine Wurmser, Madlaina von Hösslin, and Dietmar Zehn
PNAS October 1, 2019 116 (40) 20070-20076; first published September 17, 2019; https://doi.org/10.1073/pnas.1902701116
Kristiyan Kanev
aDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;
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  • ORCID record for Kristiyan Kanev
Ming Wu
aDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;
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Antar Drews
aDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;
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Patrick Roelli
aDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;
bBioinformatics Core Facility, Swiss Institute of Bioinformatics, University of Lausanne 1015 Lausanne, Switzerland;
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Christine Wurmser
cDivision of Animal Breeding, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany
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Madlaina von Hösslin
aDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;
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Dietmar Zehn
aDivision of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;
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  • For correspondence: dietmar.zehn@tum.de
  1. Edited by Arlene H. Sharpe, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, and approved August 27, 2019 (received for review February 15, 2019)

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Significance

Effector CD8 T cell responses in chronic infection and cancer are maintained by proliferation-competent progenitors, which share features with the progenitors of memory T cells in acutely resolved infections. Combining classical assessment of population dynamics with single-cell RNA sequencing, we discovered a switch in the need for CD4 help between related populations in acute and chronic infection. While in acute infection, memory T cells but not effector T cells are CD4 help dependent, and we found the opposite in chronic infection. Thus, progenitor cells in chronic infection acquire a level of autonomous function that is not seen among their counterparts in acute infection. Vice versa, the dependece of the effector cells highlight why a functional antigen-specific CD4 T cell compartment is critical in therapeutic settings.

Abstract

T cell maintenance in chronic infection and cancer follows a hierarchical order. Short-lived effector CD8 T cells are constitutively replaced from a proliferation-competent Tcf1-expressing progenitor population. This occurs spontaneously at low levels and increases in magnitude upon blocking PD-1 signaling. We explore how CD4 T cell help controls transition and survival of the progenitors and their progeny by utilizing single-cell RNA sequencing. Unexpectedly, absence of CD4 help caused reductions in cell numbers only among terminally differentiated cells while proliferation-competent progenitor cells remained unaffected with regard to their numbers and their overall phenotype. In fact, upon restoration of a functional CD4 compartment, the progenitors began to regenerate the effector CD8 T cells. Thus, unlike memory T cells for which secondary expansion requires CD4 T cell help, this is not a necessity for proliferation-competent progenitor cells in dysfunctional populations. Our data therefore reveals that proliferation-competent cells in dysfunctional populations show a previously unrecognized uncoupling of CD4 T cell help that is otherwise required by conventional memory T cells.

  • CD4 help
  • CD8 T cells
  • chronic infection
  • single-cell RNA sequencing
  • Tcf1

Footnotes

  • ↵1To whom correspondence may be addressed. Email: dietmar.zehn{at}tum.de.
  • Author contributions: K.K. and D.Z. designed research; K.K., M.W., A.D., P.R., C.W., and M.v.H. performed research; K.K. and D.Z. analyzed data; and K.K. and D.Z. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: Source single-cell RNA-seq datasets are available at Gene Expression Omnibus database (accession no. GSE137007).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1902701116/-/DCSupplemental.

Published under the PNAS license.

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Proliferation-competent Tcf1+ CD8 T cells in dysfunctional populations are CD4 T cell help independent
Kristiyan Kanev, Ming Wu, Antar Drews, Patrick Roelli, Christine Wurmser, Madlaina von Hösslin, Dietmar Zehn
Proceedings of the National Academy of Sciences Oct 2019, 116 (40) 20070-20076; DOI: 10.1073/pnas.1902701116

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Proliferation-competent Tcf1+ CD8 T cells in dysfunctional populations are CD4 T cell help independent
Kristiyan Kanev, Ming Wu, Antar Drews, Patrick Roelli, Christine Wurmser, Madlaina von Hösslin, Dietmar Zehn
Proceedings of the National Academy of Sciences Oct 2019, 116 (40) 20070-20076; DOI: 10.1073/pnas.1902701116
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