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

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.
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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- Biological Sciences
- Immunology and Inflammation