Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis

Serwas, Nina K.; Hoeger, Birgit; Ardy, Rico Chandra; Stulz, Sigrun V.; Sui, Zhenhua; Memaran, Nima; Meeths, Marie; Krolo, Ana; Petronczki, Özlem Yüce; Pfajfer, Laurène; Hou, Tie Zheng; Halliday, Neil; Santos-Valente, Elisangela; Kalinichenko, Artem; Kennedy, Alan; Mace, Emily M.; Mukherjee, Malini; Tesi, Bianca; Schrempf, Anna; Pickl, Winfried F.; Loizou, Joanna I.; Kain, Renate; Bidmon-Fliegenschnee, Bettina; Schickel, Jean-Nicolas; Glauzy, Salomé; Huemer, Jakob; Garncarz, Wojciech; Salzer, Elisabeth; Pierides, Iro; Bilić, Ivan; Thiel, Jens; Priftakis, Peter; Banerjee, Pinaki P.; Förster-Waldl, Elisabeth; Medgyesi, Dávid; Huber, Wolf‐Dietrich; Orange, Jordan S.; Meffre, Eric; Sansom, David M.; Bryceson, Yenan T.; Altman, Amnon; Boztuğ, Kaan

doi:10.1038/s41467-019-10812-x

Cited by 57 publications

(56 citation statements)

References 67 publications

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“…Def6 deficient female mice on a mixed 129/BL6 background develop a lupus-like syndrome ( Biswas et al, 2010 ; Fanzo et al, 2006 ). Def6 is a new systemic lupus erythematosus (SLE) risk variant ( Sun et al, 2016 ) and recent evidence obtained from patients show a critical role for Def6 in autoimmunity ( Serwas et al, 2019 ). In addition to the role for Def6 in immune diseases, recent GWAS study identifies DEF6 as a novel loci associated with BMD ( Pei et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

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Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis

Deng

Inoue

et al. 2020

eLife

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Bone remodeling involves a balance between bone resorption and formation. The mechanisms underlying bone remodeling are not well understood. DEF6 is recently identified as a novel loci associated with bone mineral density. However, it is unclear how Def6 impacts bone remodeling. We identify Def6 as a novel osteoblastic regulator that suppresses osteoblastogenesis and bone formation. Def6 deficiency enhances both bone resorption and osteogenesis. The enhanced bone resorption in Def6-/- mice dominates, leading to osteoporosis. Mechanistically, Def6 inhibits the differentiation of both osteoclasts and osteoblasts via a common mechanism through endogenous type-I IFN-mediated feedback inhibition. RNAseq analysis shows expression of a group of IFN stimulated genes (ISGs) during osteoblastogenesis. Furthermore, we found that Def6 is a key upstream regulator of IFNβ and ISG expression in osteoblasts. Collectively, our results identify a novel immunoregulatory function of Def6 in bone remodeling, and shed insights into the interaction between immune system and bone.

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Section: Discussionmentioning

confidence: 99%

“…Def6 deficient mice crossed with TCR transgenic DO11.10 mice develop RA-like joint disease with bone erosion ( Chen et al, 2008 ). Both genetic mouse models and recent evidence obtained from patients ( Serwas et al, 2019 ; Sun et al, 2016 ; Yi et al, 2017 ; Manni et al, 2018 ) show a critical role for Def6 in autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis

Deng

Inoue

et al. 2020

eLife

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“…BACH2 is highly expressed in resting tTreg to maintain their quiescence, and is downregulated by activation [114,115]. Finally, defects in regular tTreg development and function have been observed in patients with mutations of the beta subunit of the IL-2 receptor (CD122) or DEF6, which is involved in CTLA4 membrane trafficking [116][117][118].…”

Section: Primary Defects Of the Lymphoid Lineage In The Generation Of Ttregsmentioning

confidence: 99%

Thymic origins of autoimmunity—lessons from inborn errors of immunity

Bacchetta

Weinberg

2021

Semin Immunopathol

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During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.

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“…The reduction of available CTLA-4 on the T-cell surface is the common end point of (i) aberrant CTLA-4 protein (i.e., due to truncated CTLA-4 protein, defects in the ligand-binding domain, or homodimerization) caused by heterozygous mutations in CTLA-4 or (ii) enhanced CTLA-4 lysosomal degradation generated by biallelic mutations in LRBA or DEF6 ( Figure 1 ). Although some missense mutations in CTLA-4 do not affect the CTLA-4 protein expression, most mutations in CTLA-4, LRBA , and DEF6 reduce CTLA-4 protein levels by 50, 50–75, and 50%, respectively ( 9 , 16 , 27 , 28 ). In addition, regardless of the mutations in CTLA-4, LRBA , and DEF6 , Tregs and activated conventional T (Tcon) cells present with an overall but variable reduction in CTLA-4-dependent transendocytosis.…”

Section: Introductionmentioning

confidence: 98%

“…This process depletes the amount of co-stimulatory signals present on the APC's surface, controlling T-cell activation. While the interaction between CTLA-4 and the adaptor protein complex 2 (AP-2) directs the lysosomal degradation of the bound B7 ligands, DEF6 and LRBA essentially control the recycling fate of the CTLA-4 CCVs ( 15 , 16 ). Upon T-cell activation, mechanistic effects cause LRBA to be intracellularly expressed in Rab11 + vesicles, where it binds to the YVKM motif of the cytoplasmic tail of CTLA-4–the same binding site of AP-2.…”

Section: Introductionmentioning

confidence: 99%

Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies

Gámez-Díaz

Seidel

2021

Front. Pediatr.

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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that is constitutively expressed in regulatory T (Treg) cells. Following T-cell activation, CTLA-4 is rapidly mobilized from its intracellular vesicle pool to the cell surface to control the availability of co-stimulatory B7 molecules, thereby maintaining immune homeostasis. Heterozygous mutations in CTLA-4 lead to defects in (i) CTLA-4 ligand binding, (ii) homo-dimerization, (iii) B7-transendocytosis, and (iv) CTLA-4 vesicle trafficking, resulting in an inborn error of immunity with predominant autoimmunity. CTLA-4 vesicle trafficking impairment is also observed in patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency or the differentially expressed in FDCP6 homolog (DEF6) deficiency, caused by biallelic mutations in LRBA and DEF6, respectively. Therefore, patients with CTLA-4 insufficiency, LRBA deficiency, and—most recently reported—DEF6 deficiency present an overlapping clinical phenotype mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4. In this paper, we describe the clinical phenotypes of these immune checkpoint defects, their patho-mechanisms, and visually compare them to other immune regulatory disorders (IPEX syndrome, CD27, and CD70 deficiencies) by using the immune deficiency and dysregulation (IDDA version 2.1) “kaleidoscope” score. This illustrates the variability of the degrees and manifestations of immune deficiency and dysregulation. Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening. Furthermore, these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin's lymphoma. Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation. This mini-review highlights the most relevant biological and clinical features as well as treatment options for CTLA-4 insufficiency and LRBA and DEF6 deficiencies.

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Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis

Cited by 57 publications

References 67 publications

Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis

Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis

Thymic origins of autoimmunity—lessons from inborn errors of immunity

Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies

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