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PMID:24012345

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Citation

Xiao, J, Liu, C, Li, G, Peng, S, Hu, J, Qu, L, Lv, P, Zhang, Y, Ma, D and Chen, Y (2013) PDCD5 negatively regulates autoimmunity by upregulating FOXP3(+) regulatory T cells and suppressing Th17 and Th1 responses. J. Autoimmun. 47:34-44

Abstract

Maintenance of FOXP3 protein expression is crucial for differentiation and maturation of regulatory T (Treg) cells, which play important roles in immune homeostasis and immune tolerance. We demonstrate here that PDCD5 interacts with FOXP3, increases acetylation of FOXP3 in synergy with Tip60 and enhances the repressive function of FOXP3. In PDCD5 transgenic (PDCD5tg) mice, overexpression of PDCD5 enhanced the level of FOXP3 protein and percentage of CD4(+)CD25(+)FOXP3(+) cells. Naïve CD4(+) T cells from PDCD5tg mice were more sensitive to TGF-β-induced Treg polarization and expansion. These induced Tregs retained normal suppressive function in vitro. Severity of experimentally-induced autoimmune encephalomyelitis (EAE) in PDCD5tg mice was significantly reduced relative to that of wild-type mice. The beneficial effect of PDCD5 likely resulted from increases of Treg cell frequency, accompanied by a reduction of the predominant pathogenic Th17/Th1 response. Activation-induced cell death enhanced by PDCD5 was also linked to this process. This is the first report revealing that PDCD5 activity in T cells suppresses autoimmunity by modulating Tregs. This study suggests that PDCD5 serves as a guardian of immunological functions and that the PDCD5-FOXP3-Treg axis may be a therapeutic target for autoimmunity.

Links

PubMed Online version:10.1016/j.jaut.2013.08.002

Keywords

Acetylation; Animals; Antigens, CD4/immunology; Apoptosis/immunology; Apoptosis Regulatory Proteins/biosynthesis; Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins/immunology; Autoimmunity/immunology; Cell Differentiation/immunology; Cell Line; Cell Proliferation; Encephalomyelitis, Autoimmune, Experimental/immunology; Encephalomyelitis, Autoimmune, Experimental/therapy; Female; Forkhead Transcription Factors/immunology; Forkhead Transcription Factors/metabolism; HEK293 Cells; Histone Acetyltransferases/genetics; Histone Acetyltransferases/immunology; Humans; Interleukin-2 Receptor alpha Subunit/immunology; Lymphocyte Activation/immunology; Lymphocyte Count; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis/immunology; Multiple Sclerosis/therapy; Neoplasm Proteins/biosynthesis; Neoplasm Proteins/genetics; Neoplasm Proteins/immunology; RNA Interference; RNA, Small Interfering; T-Lymphocytes, Regulatory/immunology; Th1 Cells/immunology; Th17 Cells/immunology; Trans-Activators/genetics; Trans-Activators/immunology; Transforming Growth Factor beta/immunology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PDCD5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BZS1

F

Seeded From UniProt

complete

HUMAN:PDCD5

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PDCD5

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q9BZS1)

Seeded From UniProt

complete

HUMAN:PDCD5

enables

GO:0010698: acetyltransferase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:Q92993)

Seeded From UniProt

complete

HUMAN:PDCD5

involved_in

GO:0071560: cellular response to transforming growth factor beta stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KAT5

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KAT5

involved_in

GO:1901985: positive regulation of protein acetylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q9BZS1)

Seeded From UniProt

complete

HUMAN:FOXP3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14737

F

Seeded From UniProt

complete

HUMAN:FOXP3

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KAT5

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KAT5

involved_in

GO:1901985: positive regulation of protein acetylation

ECO:0000314: direct assay evidence used in manual assertion

P

has_input:(UniProtKB:Q9BZS1)

Seeded From UniProt

complete

HUMAN:FOXP3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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