FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease.

Abstract:

:We have found that FOXP3 is an oligomeric component of a large supramolecular complex. Certain FOXP3 mutants with single amino acid deletions in the leucine zipper domain of FOXP3 are associated with the X-linked autoimmunity-allergic dysregulation (XLAAD) and immunodysregulation, polyendocrinopathy and enteropathy, X-linked (IPEX) syndrome in humans. We report that the single amino acid deletion found in human XLAAD/IPEX patients within the leucine zipper domain of FOXP3 does not disrupt its ability to join the larger protein complex, but eliminates FOXP3 homo-oligomerization as well as heteromerization with FOXP1. We found that the zinc finger-leucine zipper domain region of FOXP3 is sufficient to mediate both homodimerization and homotetramerization. However, the same domain region from XLAAD/IPEX FOXP3 containing an E251 deletion prevents oligomerizaton and the protein remains monomeric. We also found that wild-type FOXP3 directly binds to the human IL-2 promoter, but the E251 deletion in FOXP3 in XLAAD/IPEX patient's T cells disrupts its association with the IL-2 promoter in vivo and in vitro, and limits repression of IL-2 transcription after T-cell activation. Our results suggest that compromising FOXP3 homo-oligomerization and hetero-oligomerization with the FOXP1 protein impairs DNA-binding properties leading to distinct biochemical phenotypes in humans with the XLAAD/IPEX autoimmune syndrome. This study explains some features of the pathogenesis of a disease syndrome that arises as a consequence of specific assembly failure of a transcriptional repressor due to certain mutations within the FOXP3 leucine zipper.

journal_name

Int Immunol

journal_title

International immunology

authors

Li B,Samanta A,Song X,Iacono KT,Brennan P,Chatila TA,Roncador G,Banham AH,Riley JL,Wang Q,Shen Y,Saouaf SJ,Greene MI

doi

10.1093/intimm/dxm043

subject

Has Abstract

pub_date

2007-07-01 00:00:00

pages

825-35

issue

7

eissn

0953-8178

issn

1460-2377

pii

dxm043

journal_volume

19

pub_type

杂志文章
  • Arid5a-deficient mice are highly resistant to bleomycin-induced lung injury.

    abstract::Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are among the major causes of death worldwide due to acute inflammation in the lung. AT-rich interactive domain-containing 5a (Arid5a) is an RNA-binding protein involved in inflammatory autoimmune disease through post-transcriptional control of Il6...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxx004

    authors: Dubey PK,Masuda K,Nyati KK,-Uz Zaman MM,Chalise JP,Millrine D,Kai W,Ripley B,Kishimoto T

    更新日期:2017-02-01 00:00:00

  • CCR1 expression and signal transduction by murine BMMC results in secretion of TNF-alpha, TGFbeta-1 and IL-6.

    abstract::Chemokine receptors (CCRs) are important co-stimulatory molecules found on many blood cells and associated with various diseases. The expression and function of CCRs on mast cells has been quite controversial. In this study, we report for the first time that murine bone marrow-derived mast cells (BMMC) express messeng...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxp066

    authors: Fifadara NH,Aye CC,Raghuwanshi SK,Richardson RM,Ono SJ

    更新日期:2009-08-01 00:00:00

  • Schnurri-2 regulates Th2-dependent airway inflammation and airway hyperresponsiveness.

    abstract::Schnurri (Shn)-2 is a large zinc finger-containing protein, which plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient (Shn-2(-/-)) CD4 T cells, the activation of nuclear factor-kappaB is up-regulated and their ability to differentiate into Th2 is enhanced. Here, we ...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxm042

    authors: Iwamura C,Kimura MY,Shinoda K,Endo Y,Hasegawa A,Yamashita M,Nakayama T

    更新日期:2007-06-01 00:00:00

  • Characterization of constitutive and strain-dependent subsets of CD45RA+ cells in the thymus.

    abstract::We have previously shown that the occurrence of CD45RA+ adult mouse thymocytes is strain-dependent, e.g. constituting approximately 0.6% in C57BL/Icrf and approximately 2.5% in BALB/c (Huby, R. and Goff, L., 1992. Eur. J. Immunol. 22:1659). Here we show that irrespective of strain, the thymus contains approximately 0....

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/4.11.1303

    authors: Goff LK,Huby RD

    更新日期:1992-11-01 00:00:00

  • Major population differences in T cell response to a malaria sporozoite vaccine candidate.

    abstract::Using a complete series of overlapping peptides, we have identified the T cell epitopes of a malaria vaccine candidate, the circumsporozoite (CS) protein, that are recognized by sporozoite-exposed residents of a non-endemic country. This protein and subunits from it are being considered as malaria sporozoite vaccine c...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/2.10.945

    authors: Zevering Y,Houghten RA,Frazer IH,Good MF

    更新日期:1990-01-01 00:00:00

  • A pro-inflammatory role of Fcα/μR on marginal zone B cells in sepsis.

    abstract::Fc receptors play important roles for a wide array of immune responses. In contrast to the well-defined Fcγ and Fcε receptors, the molecular and functional characteristics of Fc receptors for IgA and IgM have remained incompletely understood for years. Recent progress has unveiled the characteristics of Fc receptors f...

    journal_title:International immunology

    pub_type: 杂志文章,评审

    doi:10.1093/intimm/dxx059

    authors: Shibuya A,Honda SI,Shibuya K

    更新日期:2017-12-30 00:00:00

  • Aromatic side-chain interactions as the origin of immunological diversity in the TyrTyrGluGlu and TyrGluTyrGlu epitopes: NMR and fluorescence evidence.

    abstract::Spectroscopic methods have been applied to elucidate conformational differences responsible for the immunological diversity of two synthetic multichain copolymers, Tyr1Tyr2Glu3Glu4-poly-DL-Ala--poly-Lys and Tyr1Glu2Tyr3Glu4-poly-DL-Ala--poly-Lys. Despite their far-reaching structural similarity in the epitope peptide ...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/5.6.591

    authors: Muszkat KA,Schechter B,Sela M

    更新日期:1993-06-01 00:00:00

  • Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behçet's syndrome patients.

    abstract::Behçet's syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Features of both innate and adaptive immunity have been claimed in the pathogenesis of BS. To test the possible dysregulation of the NLRP3/cryopyrin (Nod-like receptor with a pyrin domain 3) inflammasome, as a result of mutation(s), we p...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxt046

    authors: Yüksel Ş,Eren E,Hatemi G,Sahillioğlu AC,Gültekin Y,Demiröz D,Akdiş C,Fresko İ,Özören N

    更新日期:2014-02-01 00:00:00

  • TCR v(beta) usage and clonality of T cells isolated from progressing and rejected tumor sites before and after in vitro culture.

    abstract::A gelatin sponge model of concomitant tumor immunity was employed in order to examine the clonality of T cells associated with progressing and rejected tumor sites. Here we show that freshly isolated T cells bearing TCR V(beta)1, CDR3 RPGTGN, J(beta)1.1 and TCR V(beta)8, CDR3 GD, J(beta)1.6 predominated progressing an...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/12.5.639

    authors: Kurt RA,Park JA,Schluter SF,Marchalonis JJ,Akporiaye ET

    更新日期:2000-05-01 00:00:00

  • The exploitation of distinct recognition receptors in dendritic cells determines the full range of host immune relationships with Candida albicans.

    abstract::Dendritic cells (DC) sense saprophytic yeast and pathogenic, filamentous forms of Candida albicans in a specific way, resulting in disparate patterns of DC and T(h) cell activation. Using human and murine DC, such disparate patterns could be traced to the exploitation of distinct recognition receptors. Although usage ...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxh012

    authors: Romani L,Montagnoli C,Bozza S,Perruccio K,Spreca A,Allavena P,Verbeek S,Calderone RA,Bistoni F,Puccetti P

    更新日期:2004-01-01 00:00:00

  • A high frequency of hybridomas from M54 mu heavy chain transgenic mice initially co-express transgenic and rearranged endogenous mu genes.

    abstract::The M54 transgenic mouse line, which carries the 17.2.25 Ig mu heavy chain gene, rearranges Ig heavy chains and expresses both transgenic and endogenous mu. B cell lineage development is selectively impaired in these mice and cells that simultaneously express transgenic and endogenous mu ('double-producers') are commo...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/5.9.1011

    authors: Lam KP,Herzenberg LA,Stall AM

    更新日期:1993-09-01 00:00:00

  • Interleukin 12 alters the isotype-restricted antibody response of mice to hen eggwhite lysozyme.

    abstract::Protein antigens elicit humoral responses in mice that consist predominantly of IgG1 antibodies. We have now investigated the ability of IL-12, a cytokine reported to augment IgG2a anti-hapten responses through activation of Th1 cells, to alter antibody responses to hen eggwhite lysozyme (HEL). The normal response of ...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/7.9.1519

    authors: Buchanan JM,Vogel LA,Van Cleave VH,Metzger DW

    更新日期:1995-09-01 00:00:00

  • A model of suppression of the antigen-specific CD4 T cell response by regulatory CD25+CD4 T cells in vivo.

    abstract::Despite intense recent interest, the suppressive mechanisms of regulatory CD25+CD4 T cells remain poorly understood. One deficiency in the field is the lack of in vivo models where the effects of regulatory CD25+CD4 T cells on antigen-specific responder T cells can be measured quantitatively. We describe one such mode...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxh213

    authors: Thorstenson KM,Herzovi L,Khoruts A

    更新日期:2005-04-01 00:00:00

  • Translocation of tyrosine-phosphorylated TCRzeta chain to glycolipid-enriched membrane domains upon T cell activation.

    abstract::Recent studies point to glycolipid-enriched membrane (GEM) microdomains as the critical sites for TCR-mediated signal transduction. However, whether the TCR complex is localized in the GEM domain is not well-defined. In the present study, we analyzed localization of the TCR-CD3 complex in the GEM domain by isolating t...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/11.9.1395

    authors: Kosugi A,Saitoh S,Noda S,Yasuda K,Hayashi F,Ogata M,Hamaoka T

    更新日期:1999-09-01 00:00:00

  • The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation.

    abstract::The CD2 co-receptor expressed on the surface of T lymphocytes is able to stimulate T cell activation, proliferation and cytokine production in the absence of direct engagement of the antigen-specific TCR. Engagement of human CD2 by mitogenic pairs of anti-CD2 mAb induces tyrosine phosphorylation of a number of intrace...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/13.1.13

    authors: Lin H,Martelli MP,Bierer BE

    更新日期:2001-01-01 00:00:00

  • Paradoxical alteration of acute-phase protein levels in patients with chronic hepatitis C treated with IFN-alpha2b.

    abstract::Previously we observed elevation of the serum concentration of two acute-phase protein (AFP) complement components (C9 and C1-inhibitor) in patients with chronic hepatitis C who responded (R) to IFN-alpha therapy, but not in non-responders (NR). In the present study we investigated the effect of high-dose IFN-alpha th...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxh024

    authors: Kalabay L,Nemesánszky E,Csepregi A,Pusztay M,Dávid K,Horváth G,Ibrányi E,Telegdy L,Pár A,Bíró A,Fekete B,Gervain J,Horányi M,Ribiczey P,Csöndes M,Kleiber M,Walentin S,Prohászka Z,Füst G

    更新日期:2004-01-01 00:00:00

  • Differential effect of insulin and elevated glucose level on adenosine transport in rat B lymphocytes.

    abstract::Impaired lymphocyte function is a common feature of human diabetes. Nucleoside transport across the plasma membrane is an essential step during lymphocyte growth and activation. In our study, we evaluated the impact of diabetic conditions on nucleoside transport system in B lymphocytes. Examination of the nucleoside t...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxh195

    authors: Sakowicz M,Szutowicz A,Pawelczyk T

    更新日期:2005-02-01 00:00:00

  • TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection.

    abstract::To investigate the role of the Toll-like receptor (TLR) family in host defense against Toxoplasma gondii, we infected TLR2-, TLR4- and MyD88-deficient mice with the avirulent cyst-forming Fukaya strain of T. gondii. All TLR2- and MyD88-deficient mice died within 8 days, whereas all TLR4-deficient and wild-type mice su...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxg108

    authors: Mun HS,Aosai F,Norose K,Chen M,Piao LX,Takeuchi O,Akira S,Ishikura H,Yano A

    更新日期:2003-09-01 00:00:00

  • Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells.

    abstract::Naturally arising CD25(+)CD4(+) regulatory T (T(R)) cells can be exploited to establish immunologic tolerance to non-self antigens. In vivo exposure of CD25(+)CD4(+) T cells from normal naive mice to alloantigen in a T cell-deficient environment elicited spontaneous expansion of alloantigen-specific CD25(+)CD4(+) T(R)...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxh122

    authors: Nishimura E,Sakihama T,Setoguchi R,Tanaka K,Sakaguchi S

    更新日期:2004-08-01 00:00:00

  • Class I-restricted cytotoxic T cell recognition of split peptide ligands.

    abstract::We developed a novel approach to probe the molecular basis of TCR recognition of the MHC class I-peptide complex and to determine how constraints placed on peptide binding by the class I molecule influence T cell recognition. We synthesized peptide pairs derived from the N- and C-terminal regions of class I peptide li...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/9.1.81

    authors: Gillanders WE,Hanson HL,Rubocki RJ,Hansen TH,Connolly JM

    更新日期:1997-01-01 00:00:00

  • Characterization of an active, non-myristylated, cytoplasmic form of the lymphoid protein tyrosine kinase pp56lck.

    abstract::pp56lck is a member of the src family of tyrosine kinases mainly expressed in T lymphocytes. Src tyrosine kinases have been implicated in the control of cell growth and differentiation in different cell types, but the mechanism of regulation of these enzymes is poorly understood. In order to characterize the distinct ...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/3.7.673

    authors: Carrera AC,Li P,Roberts TM

    更新日期:1991-07-01 00:00:00

  • The extended substrate specificity of the human mast cell chymase reveals a serine protease with well-defined substrate recognition profile.

    abstract::The human chymase (HC) is a major granule constituent of mast cells (MCs) residing in the connective tissue and the sub-mucosa. Although many potential substrates have been described for this important MC enzyme, its full range of in vivo substrates has most likely not yet been identified. A major step toward a better...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxn128

    authors: Andersson MK,Enoksson M,Gallwitz M,Hellman L

    更新日期:2009-01-01 00:00:00

  • CD4+CD25+ regulatory T cells are activated in vivo by recognition of self.

    abstract::Naturally occurring CD4(+)CD25(+) regulatory T cells (nT(R)) comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. Here we demonstrate that the level of phosphorylation of the TCR zeta-chain is approximately 1.5- to 4-fold higher in nT(R) as compared with CD4(+)CD25...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxm021

    authors: Andersson J,Stefanova I,Stephens GL,Shevach EM

    更新日期:2007-04-01 00:00:00

  • Longitudinal analysis of T cells responding to tetanus toxoid in healthy subjects as well as in pediatric patients after bone marrow transplantation: the identification of identical TCR-CDR3 regions in time suggests long-term stability of at least part of

    abstract::To understand the nature of long-term Th immune responses, we investigated in the present study the TCRBV gene repertoire of CD4(+) T cells specific for the recall antigen tetanus toxoid (TT) in recipients of an allogeneic bone marrow transplantation (allo-BMT) at several time points after transplantation and in their...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/13.4.507

    authors: Godthelp BC,van Tol MJ,Vossen JM,van den Elsen PJ

    更新日期:2001-04-01 00:00:00

  • Differential antibody binding to the surface alphabetaTCR.CD3 complex of CD4+ and CD8+ T lymphocytes is conserved in mammals and associated with differential glycosylation.

    abstract::We have previously shown that the surface alphabeta T cell antigen receptor (TCR).CD3 complex borne by human CD4(+) and CD8(+) T lymphocytes can be distinguished using mAbs. Using two unrelated sets of antibodies, we have now extended this finding to the surface alphabetaTCR.CD3 of seven additional mammalian species (...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxn081

    authors: Rossi NE,Reiné J,Pineda-Lezamit M,Pulgar M,Meza NW,Swamy M,Risueno R,Schamel WW,Bonay P,Fernández-Malavé E,Regueiro JR

    更新日期:2008-10-01 00:00:00

  • Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response.

    abstract::CD70 and CD80 are co-stimulatory molecules which belong to the tumor necrosis factor family and the B7 family respectively. When they are co-expressed by gene-modified TS/A tumor cells, they provide an efficient protective and long-lasting T-dependent antitumor response. We first showed that when CD70 and CD80 were de...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxg038

    authors: Douin-Echinard V,Péron JM,Lauwers-Cancès V,Favre G,Couderc B

    更新日期:2003-03-01 00:00:00

  • The role of immune cells in brain development and neurodevelopmental diseases.

    abstract::During brain development, the generation of neurons and glial cells is rigorously regulated by diverse mechanisms including the immune system. Dysfunction of the developing system results in the onset of neurodevelopmental disorders and psychological disorders. Recent studies have demonstrated that the immune system i...

    journal_title:International immunology

    pub_type: 杂志文章,评审

    doi:10.1093/intimm/dxy041

    authors: Tanabe S,Yamashita T

    更新日期:2018-09-25 00:00:00

  • FcγRIIIA-mediated activation of NK cells by IgG heavy chain complexed with MHC class II molecules.

    abstract::Natural killer (NK) cells are a major FcγRIIIA-expressing lymphocyte population that mediate antibody-dependent cellular cytotoxicity. Although NK cells are critical for immunity against viruses and tumors, they are also activated in the joints of patients with rheumatoid arthritis (RA) and may be involved in disease ...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/dxz010

    authors: Shimizu Y,Kohyama M,Yorifuji H,Jin H,Arase N,Suenaga T,Arase H

    更新日期:2019-04-26 00:00:00

  • Interleukin 10 inhibits T cell alloreaction induced by human dendritic cells.

    abstract::Human dendritic cells (DC) generated from CD34+ hematopoietic progenitors cultured in the presence of granulocyte macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha are related to Langerhans cells (DLC) and have been shown to induce a strong proliferation of allogeneic CD4+ T cells. Th...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/6.8.1177

    authors: Caux C,Massacrier C,Vanbervliet B,Barthelemy C,Liu YJ,Banchereau J

    更新日期:1994-08-01 00:00:00

  • Developmental control of antigen-induced thymic transcription factors.

    abstract::Antigen engagement of the TCR may lead to activation of mature T cells while inducing deletion or positive selection of immature thymocytes. Using thymocytes from TCR transgenic mice recognizing the allo-antigen H-2Kb we investigated whether double-positive CD4+CD8+ (DP) thymocytes constitute a particular developmenta...

    journal_title:International immunology

    pub_type: 杂志文章

    doi:10.1093/intimm/8.9.1421

    authors: Simon AK,Auphan N,Schmitt-Verhulst AM

    更新日期:1996-09-01 00:00:00