TY - JOUR
T1 - Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells
AU - Nolz, Jeffrey C.
AU - Rai, Deepa
AU - Badovinac, Vladimir P.
AU - Harty, John T.
PY - 2012/4/17
Y1 - 2012/4/17
N2 - Infection or successful vaccination results in the formation of long-lived memory CD8 T-cell populations. Despite their numerical stability, memory CD8 T-cell populations are thought to completely turn over through proliferation within a 2- to 3-mo period. Therefore, steady-state memory cell proliferation must be balanced by a precisely regulated and equivalent death rate. However, the mechanisms regulating this balancing process remain completely undefined. Herein, we provide evidence for "death-intermediate memory cells" (TDIM) within memory CD8 T-cell populations generated by infection. Importantly, CD62L Lo/CD27 LoT DIMs are functionally characterized by an inability to produce cytokines, the failure to internalize T-cell receptor following antigenic stimulation, and signatures of apoptotic death. Furthermore, we demonstrate that, mechanistically, T DIM are directly generated from dividing "central memory" T-cell populations undergoing memory turnover in vivo. Collectively, these results demonstrate that as central memory CD8 T cells proliferate, they continuously generate a population of CD8 T cells that are nonfunctional and apoptotic; thus, our data support a model wherein division-linked generation of T DIM contributes to numerically stable CD8 T-cell memory.
AB - Infection or successful vaccination results in the formation of long-lived memory CD8 T-cell populations. Despite their numerical stability, memory CD8 T-cell populations are thought to completely turn over through proliferation within a 2- to 3-mo period. Therefore, steady-state memory cell proliferation must be balanced by a precisely regulated and equivalent death rate. However, the mechanisms regulating this balancing process remain completely undefined. Herein, we provide evidence for "death-intermediate memory cells" (TDIM) within memory CD8 T-cell populations generated by infection. Importantly, CD62L Lo/CD27 LoT DIMs are functionally characterized by an inability to produce cytokines, the failure to internalize T-cell receptor following antigenic stimulation, and signatures of apoptotic death. Furthermore, we demonstrate that, mechanistically, T DIM are directly generated from dividing "central memory" T-cell populations undergoing memory turnover in vivo. Collectively, these results demonstrate that as central memory CD8 T cells proliferate, they continuously generate a population of CD8 T cells that are nonfunctional and apoptotic; thus, our data support a model wherein division-linked generation of T DIM contributes to numerically stable CD8 T-cell memory.
UR - http://www.scopus.com/inward/record.url?scp=84859977092&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859977092&partnerID=8YFLogxK
U2 - 10.1073/pnas.1118868109
DO - 10.1073/pnas.1118868109
M3 - Article
C2 - 22474367
AN - SCOPUS:84859977092
SN - 0027-8424
VL - 109
SP - 6199
EP - 6204
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -