PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.

PD-1⁺TCF-1⁺ stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)–directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1⁻ daughter cell alongside a self-renewing TCF-1⁺ sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1⁺TCF-1⁺ stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1–directed immunotherapy in humans. Editor's summary: Stem-like CD8 T cells develop during periods of persistent antigen exposure. During chronic infection and cancer, therapies can stimulate their differentiation into antigen-specific cells with effector function; yet factors controlling the integrity of the stem-like T cell pool were unknown. Studying chronic viral infection in mice, Humblin et al. found that the co-stimulatory molecule CD28 regulated metabolism of stem-like CD8 T cells expressing the inhibitory receptor PD-1 to promote self-renewal and differentiation. In companion work, Gill et al. found that PD-1 blockade, while promoting effector cell differentiation, likewise stimulated the self-renewal of these stem-like CD8 T cells, maintaining the size and functionality of the progenitor pool. Thus, immune checkpoint therapies may rejuvenate immune responses without diminishing the durability of the stem-like CD8 T cells that respond to treatment. —Sarah H. Ross [ABSTRACT FROM AUTHOR]