Sestrins induce natural killer function in senescent-like CD8

Branca I Pereira
Roel P H De Maeyer
Luciana P Covre
Djamel Nehar-Belaid, The Jackson Laboratory
Alessio Lanna
Sophie Ward
Radu Marches, The Jackson Laboratory
Emma S Chambers
Daniel C O Gomes
Natalie E Riddell
Mala K Maini
Vitor H Teixeira
Samuel M Janes
Derek W Gilroy
Anis Larbi
Neil A Mabbott
Duygu Ucar, The Jackson Laboratory
George A Kuchel
Sian M Henson
Jessica Strid
Jun H Lee
Jacques Banchereau, The Jackson Laboratory
Arne N Akbar


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.