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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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Proliferation-competent Tcf1+ CD8 T cells in dysfunctional populations are CD4 T cell help independent
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- Biological Sciences
- Immunology and Inflammation
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