Using scRNAseq in the LCMV chronic infection model, Kanev et al. surprisingly found that CD4+ T cells were not necessary for the maintenance of Tcf1+ dysfunctional effector-progenitor T cells, but were required for their differentiation into and maintenance of Tcf1- terminally differentiated effector cells. CD4+ T cell help was still necessary for effector expansion from non-dysfunctional progenitor cells. Depletion of CD4+ T cells increased PD-1 in both Tcf1+ and remaining Tcf1- CD8+ T cells, and shifted the proportions of different effector clusters. Upon reconstitution with CD4+ T cells, effector-progenitors proliferated and generated effector CD8+ T cells.

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.

Author Info: (1) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. (2) Division of Animal Physiology

Author Info: (1) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. (2) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. (3) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. (4) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. Bioinformatics Core Facility, Swiss Institute of Bioinformatics, University of Lausanne 1015 Lausanne, Switzerland. (5) Division of Animal Breeding, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. (6) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany. (7) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany; dietmar.zehn@tum.de.