Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells

The ability of activated progenitor T cells to self-renew while producing differentiated effector cell descendants may underlie immunological memory and persistent responses to ongoing infection. The nature of stem-like T cells responding to cancer and during treatment with immunotherapy is not clear. The subcellular organization of dividing progenitor CD8⁺ T cells from mice challenged with syngeneic tumors is examined here. Three-dimensional microscopy reveals an activating hub composed of polarized CD3, CD28, and phosphatidylinositol 3-kinase (PI3K) activity at the putative immunological synapse with an inhibitory hub composed of polarized PD-1 and CD73 at the opposite pole of mitotic blasts. Progenitor T cells from untreated and inhibitory checkpoint blockade-treated mice yield a differentiated TCF1^- daughter cell, which inherits the PI3K activation hub, alongside a discordantly fated, self-renewing TCF1⁺ sister cell. Dynamic organization of opposite activating and inhibitory signaling poles in mitotic lymphocytes may account for the enigmatic durability of specific immunity.