title: Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells.
abstract: 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" (T(DIM)) within memory CD8 T-cell populations generated by infection. Importantly, CD62L(Lo)/CD27(Lo) T(DIM)s 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.
authors.affiliation: Departments of Microbiology and Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Nolz
authors.forename: Deepa
authors.initials: D
authors.lastname: Rai
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Badovinac
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D020169:Caspases / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology / Q000502:physiology; D008088:Listeriosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019041:L-Selectin; D020169:Caspases