DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

Singh, Akhilesh K.; Eken, Ahmet; Hagin, David; Komal, Khushbu; Bhise, Gauri; Shaji, A V; Arkatkar, Tanvi; Jackson, Shaun W.; Bettelli, Estelle; Torgerson, Troy R.; Oukka, Mohamed

doi:10.1172/jci.insight.94275

Cited by 33 publications

(23 citation statements)

References 64 publications

(76 reference statements)

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“…Thus, we speculate that the relative levels of somatic reversion in T reg vs T EM cell subsets might dictate the likelihood of autoimmune disease. Consistent with this possibility, conditional knockout of Dock8 in T reg —but not ubiquitous knockout of Dock8 —causes multiorgan autoimmune disease in mice by impairing IL‐2 signaling in T reg cells . In our model, we propose that autoimmunity would be less likely in any given patient when somatic reversions occur to a greater level in T reg as compared to T EM cells.…”

Section: Autoimmunitysupporting

confidence: 60%

“…Consistent with this possibility, conditional knockout of Dock8 in T reg -but not ubiquitous knockout of Dock8-causes multiorgan autoimmune disease in mice by impairing IL-2 signaling in T reg cells. 74,75 In our model, we propose that autoimmunity would be less likely in any given patient when somatic reversions occur to a greater level in T reg as compared to T EM cells. On the other hand, autoimmunity would be more likely in any given patient when somatic reversions occur to a lesser level in T reg as compared to T EM .…”

Section: Allerg I C D Is E a S Ementioning

confidence: 99%

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Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Jing

Angelus

et al. 2018

Immunological Reviews

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Summary: DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring 1) profound susceptibility to virus infections of the skin, with associated skin cancers, and 2) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.

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Section: Autoimmunitysupporting

confidence: 60%

Section: Allerg I C D Is E a S Ementioning

confidence: 99%

Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Jing

Angelus

et al. 2018

Immunological Reviews

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“…In mice, this defect was not rescued by normal T cells, implying that it was intrinsic to Dock8-deficient B cells. The survival defect was found not only in Dock8-deficient MZB cells, but also in many other cell types, including T cells [159, 160], NKT cells [161], Tregs [162, 163], and ILCs [164]. Studies of these defects in mice have helped to explain the wide spectrum of pathogens to which DOCK8-deficient patients are susceptible.…”

Section: Dock8 Deficiencymentioning

confidence: 99%

Human hyper-IgE syndrome: singular or plural?

et al. 2018

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Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50 years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term "HIES" to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

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“…DOCK8 deficient patients have a defect in the peripheral B cell checkpoint associated with reduced Treg cell percentages and impaired Treg cell in vitro suppressive ability . While Dock8 −/− mice do not develop spontaneous autoimmunity or inflammation, mice lacking DOCK8 specifically in Treg cells do . These mice have hyperactivation of their T cells with increased production of pro‐inflammatory cytokines.…”

Section: Human Disease Caused By Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

“…DOCK8 deficient Treg cells have an in vivo competitive disadvantage and poor in vivo suppressive activity. DOCK8 interacts with STAT5, and DOCK8 deficient Treg cells have abnormalities in phosphorylation of STAT5 downstream of IL‐2 . DOCK8 is important for TCR driven actin polymerization and stability of the IS in Treg cells …”

Section: Human Disease Caused By Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

Primary immunodeficiencies caused by mutations in actin regulatory proteins

Janssen

2018

Immunological Reviews

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Summary The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients’ mutations and generation of mouse models that recapitulate the patients’ phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.

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DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

Cited by 33 publications

References 64 publications

Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Human hyper-IgE syndrome: singular or plural?

Primary immunodeficiencies caused by mutations in actin regulatory proteins

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