Disruptors of sestrin-MAPK interactions rejuvenate T cells and expand TCR specificity

Summary Whereas treatments that reactivate exhausted T cells are available, strategies to rejuvenate terminally differentiated senescent lymphocytes are yet to be developed. Senescent T cells, with short telomeres and inactive telomerase, are different from exhausted cells, and may form due to defective telomere transfer reactions upon contact with antigen presenting cells (APCs). Senescent T cells are characterized by presence of sestrin-MAPK kinase activation complexes (sMACs), large immune-inhibitory protein assemblies of sestrins bound to a stress/energy sensing kinase (AMPK) and three functional effector kinases (ERK, JNK and p38 MAPKs). Here we described first in class Disruptors of the Sestrin-MAPK immune-inhibitory Complex (DOS), which target sMAC to ubiquitin-dependent proteasomal degradation, resulting in long-term sestrin transcriptional inhibition, increased T cell fitness, and generation of long-lived stem like memory features. Strikingly, the DOS generated stem T cells present de novo antigen-specific T-cell receptor DNA rearrangements that precede their future expansion. Although largely senescent at the point of treatment, the DOS regenerated T cells, with stem features and new TCRs, initiated immune-protective rejuvenation-dependent responses to new challenges, with or without vaccination. Therefore, it is possible to generate new T cell clones from formerly senescent cells and expand immune specificity. Highlights DOS are the first sestrin-MAPK binding disruptors DOS rejuvenate T cells (DOS-juvenation) DOS-juvenated T cells protect old mice from lethal infections, with or without vaccination DOS-juvenated T cells exist as stem-like cells that undergo antigen-specific TCR revisions