Pereira, De Maeyer, Covre, Nehar-Belaid (co-first authors) et al. Nature Immunology. PMID:32231301
Abstract
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.
Link here
Data avalability
Accession number EGAS00001004255
Scripts
github.com/dnehar/Temra-IL7R-Senescence
Immune response during aging
To better understand the mechanisms underlying the accumulation of the highly differentiated CD8+ T cells (known as Temras) during aging, we collaborated with Dr. Arne Akbar (University College London, London, England). I used scRNA-seq to analyze the transcriptomic profiles of purified CD8+ T cells from older adults. I confirmed the observations made by our collaborators using murine models, revealing that senescent CD8+ T cells can develop NK cell-like features over time, a process that was regulated by the stress-sensing proteins called sestrins.