Regulation of memory CD8 T-cell differentiation by cyclin-dependent kinase inhibitor p27Kip1.
Induction of potent T-cell memory is the goal of vaccinations, but the molecular mechanisms that regulate the formation of memory CD8 T cells are not well understood. Despite the recognition that controls of cellular proliferation and apoptosis govern the number of memory T cells, the cell cycle regulatory mechanisms that control these key cellular processes in CD8 T cells during an immune response are poorly defined. Here, we have identified the cyclin-dependent kinase inhibitor p27(Kip1) as a critical regulator of the CD8 T-cell homeostasis at all phases of the T-cell response to an acute viral infection in mice. By acting as a timer for cell cycle exit, p27(Kip1) curtailed the programmed expansion of interleukin-2-producing memory precursors and markedly limited the magnitude and quality of CD8 T-cell memory. In the absence of p27(Kip1), CD8 T cells showed superior recall responses shortly after vaccination with recombinant Listeria monocytogenes. Additionally, we show that p27(Kip1) constrains proliferative renewal of memory CD8 T cells, especially of the effector memory subset. These findings provide critical insights into the cell cycle regulation of CD8 T-cell homeostasis and suggest that modulation of p27(Kip1) could bolster vaccine-induced T-cell memory and protective immunity.
Singh
Anju
A
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Jatzek
Anna
A
Plisch
Erin Hemmila
EH
Srinivasan
Rajini
R
Svaren
John
J
Suresh
M
M
D019264:Adoptive Transfer; D000818:Animals; D000956:Antigens, Viral / Q000008:administration & dosage; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000502:physiology; D002453:Cell Cycle / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D007156:Immunologic Memory / Q000502:physiology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000276:immunology / Q000502:physiology
D000956:Antigens, Viral; C493961:Cdkn1b protein, mouse; D007376:Interleukin-2; D050760:Cyclin-Dependent Kinase Inhibitor p27
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