Immune Checkpoints Acting as Gate-keepers of T Lymphocyte Self-renewal

Abstract

Abstract Immune checkpoint inhibition represents a promising therapeutic modality for several previously incurable cancer syndromes. Why successful T cell responses are achieved in some patients but not others is incompletely understood. Because blockade of more than one inhibitory signal is now being investigated as approach to increase the chances of therapeutic success, we investigated how combined loss of PD-1 and LAG-3 signaling in CD8+ T cells would influence a well-characterized immune response. After challenge with Vaccinia virus, T cells from mice lacking both inhibitory pathways underwent a more vigorous primary effector cell response but were severely defective during a secondary challenge. During modeled T cell activation, immune checkpoint inhibition resulted in greater production of irreversibly differentiated effector cell progeny, but this came at the expense of accelerated depletion of self-renewing progenitor cells. Pharmacological interventions that impede anabolism-associated signaling were able to correct progenitor cells loss in the face of checkpoint inhibition. Unleashing greater and greater T cell activation may result in regenerative failure of critical clones. By fostering the expansion of self-renewing progenitors, reversible agents that dampen T cell signal strength might paradoxically improve durability of immune checkpoint inhibition.