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Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.

Original publication




Journal article


Nat immunol

Publication Date





684 - 694


Adaptor Proteins, Signal Transducing, CD8-Positive T-Lymphocytes, Cellular Senescence, Cytotoxicity, Immunologic, Gene Expression Profiling, Humans, Killer Cells, Natural, Membrane Proteins, NK Cell Lectin-Like Receptor Subfamily K, Nuclear Proteins, Receptors, Antigen, T-Cell, Receptors, Natural Killer Cell, Signal Transduction, Yellow Fever, Yellow fever virus