Dedicator of cytokinesis 8–deficient CD4 +  T cells are biased to a T H 2 effector fate at the expense of T H 1 and T H 17 cells

Tangye, Stuart G.; Pillay, Bethany; Randall, Katrina L.; Avery, Danielle T.; Phan, Tri Giang; Gray, Paul; Ziegler, John B.; Smart, Joanne; Peake, Jane; Arkwright, Peter D.; Hambleton, Sophie; Orange, Jordan S.; Goodnow, Christopher C.; Uzel, Gülbû; Casanova, Jean‐Laurent; Reyes, Saúl; Freeman, Alexandra F.; Su, Helen C.; Cindy, S.

doi:10.1016/j.jaci.2016.07.016

Cited by 74 publications

(77 citation statements)

References 72 publications

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“…DOCK8-deficient patients develop Staphylococcus aureus skin abscesses, or soft tissue infections, elevated serum IgE, eosinophilia, and GI tract infections (19). A recent study has also found that memory CD4 + T cells of DOCK8-deficient patients are skewed toward Th2 cells, probably at the expense of Th1 and Th17 cells (52), which may result in a compromised antiviral and antifungal immunity.…”

Section: (L) Histogram Showing the Proliferation Of Sorted Tregs Frommentioning

confidence: 99%

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

Singh¹,

Eken²,

Hagin³

et al. 2017

JCI Insight

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Section: (L) Histogram Showing the Proliferation Of Sorted Tregs Frommentioning

confidence: 99%

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

Singh¹,

Eken²,

Hagin³

et al. 2017

JCI Insight

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“…35,36 Two recent studies found that CD4 + T cells from DOCK8-deficient patients are preferentially polarized to a T H 2 effector phenotype, with defective ability to polarize towards a T H 17 cytokine producing state. 37,38 Mechanistically, DOCK8 constitutively associates with STAT3 in CD4 + T cells in a GEF-independent manner, but promotes STAT3 activation through a GEF-dependent mechanism upon IL-6 or IL-21 stimulation. 38 Indeed, mutant cells that lack DOCK8 GEF activity, but retain protein expression, had defective T H 17 polarization.…”

Section: Regulation Of Polarization and Cytokine Productionmentioning

confidence: 99%

DOCK8 regulates signal transduction events to control immunity

2017

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Genetic mutations in the gene encoding DOCK8 cause an autosomal recessive form of hyper immunoglobulin E syndrome (AR-HIES), referred to as DOCK8 deficiency. DOCK8 deficiency in humans results in the onset of combined immunodeficiency disease (CID), clinically associated with chronic infections with diverse microbial pathogens, and a predisposition to malignancy. It is now becoming clear that DOCK8 regulates the function of diverse immune cell sub-types, particularly lymphocytes, to drive both innate and adaptive immune responses. Early studies demonstrated that DOCK8 is required for lymphocyte survival, migration and immune synapse formation, which translates to poor pathogen control in the absence of DOCK8. However, more recent advances have pointed to a crucial role for DOCK8 in regulating the signal transduction events that control transcriptional activity, cytokine production and functional polarization of immune cells. Here, we summarize recent advances in our understanding of DOCK8 function, paying particular attention to an emerging role as a signaling intermediate to promote immune responses to diverse external stimuli.

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“…DOCK8 deficiency, also classified as autosomal recessive HIES, presents with eczema, allergies (particularly to food allergens) and recurrent infections in addition to elevated IgE and eosinophilia [105]. DOCK8-deficient T cells have an intrinsic bias toward a Th2 phenotype as well as defects in Th17 differentiation through reduced STAT3 activity [106, 107]. The impaired Th17 differentiation is notable because it replicates a finding in the autosomal dominant form of HIES (AD-HIES, also known as Job’s syndrome) associated with mutations in STAT3 [108].…”

Section: Negative Regulation Of Type 2 Immune Responsesmentioning

confidence: 99%

Negative Regulation of Type 2 Immunity

Kouchkovsky

Ghosh

Rothlin

2017

Trends in Immunology

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Type 2 immunity encompasses the mechanisms through which the immune system responds to helminths and an array of environmental substances such as allergens. In the developing world, billions of individuals are chronically infected with endemic parasitic helminths. In comparison, in the industrialized world, millions of individuals suffer from dysregulated type 2 immunity, referred to clinically as atopic diseases including asthma, allergic rhinitis and atopic dermatitis. Thus, type 2 immunity must be carefully regulated to mount protective host response yet avoid inappropriate activation and immunopathology. In this review, we describe the keys players and connections at play in type 2 responses and focus on the emerging mechanisms involved in the negative regulation of type 2 immunity.

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Dedicator of cytokinesis 8–deficient CD4 + T cells are biased to a T H 2 effector fate at the expense of T H 1 and T H 17 cells

Cited by 74 publications

References 72 publications

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

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

DOCK8 regulates signal transduction events to control immunity

Negative Regulation of Type 2 Immunity

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