p27(Kip1) negatively regulates the magnitude and persistence of CD4 T cell memory.
Much is known about the differentiation of naive T cells into distinct lineages of effector cells, but the molecular mechanisms underlying the generation and maintenance of CD4 T cell memory are poorly characterized. Our studies ascribe a novel role for the cell cycle regulator p27(Kip1) as a prominent negative regulator of the establishment and long-term maintenance of Th1 CD4 T cell memory. We demonstrate that p27(Kip1) might restrict the differentiation and survival of memory precursors by increasing the T-bet/Bcl-6 ratio in effector CD4 T cells. By promoting apoptosis and contraction of effector CD4 T cells by mechanisms that are at least in part T cell intrinsic, p27(Kip1) markedly limits the abundance of memory CD4 T cells. Furthermore, we causally link p27(Kip1)-dependent apoptosis to the decay of CD4 T cell memory, possibly by repressing the expression of γ-chain receptors and the downstream effector of the Wnt/β-catenin signaling pathway, Tcf-1. We extend these findings by showing that the antagonistic effects of p27(Kip1) on CD4 T cell memory require its cyclin-dependent kinase-binding domain. Collectively, these findings provide key insights into the mechanisms underlying the governance of peripheral CD4 T cell homeostasis and identify p27(Kip1) as a target to enhance vaccine-induced CD4 T cell memory.
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Anna
A
Jatzek
Melba Marie
MM
Tejera
Anju
A
Singh
Jeremy A
JA
Sullivan
Erin H
EH
Plisch
M
M
Suresh
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D051538:Hepatocyte Nuclear Factor 1-alpha; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D051153:Wnt Proteins / Q000235:genetics / Q000276:immunology; D051176:beta Catenin / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor
C495267:CTNNB1 protein, mouse; C493961:Cdkn1b protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D051822:T Cell Transcription Factor 1; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051153:Wnt Proteins; D051176:beta Catenin; D050760:Cyclin-Dependent Kinase Inhibitor p27