Dataset Information

Dedicator of cytokinesis 8-deficient CD4⁺ T cells are biased to a T_H2 effector fate at the expense of T_H1 and T_H17 cells.

ABSTRACT:

Background

Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4⁺ T cells to disease pathogenesis in these patients has not been thoroughly investigated.

Objective

We sought to investigate the phenotype and function of DOCK8-deficient CD4⁺ T cells to determine (1) intrinsic and extrinsic CD4⁺ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency.

Methods

We performed in-depth analysis of the CD4⁺ T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4⁺ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects.

Results

DOCK8-deficient memory CD4⁺ T cells were biased toward a T_H2 type, and this was at the expense of T_H1 and T_H17 cells. In vitro polarization of DOCK8-deficient naive CD4⁺ T cells revealed the T_H2 bias and T_H17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites.

Conclusion

Investigations into the DOCK8-deficient CD4⁺ T cells provided an explanation for some of the clinical features of this disorder: the T_H2 bias is likely to contribute to atopic disease, whereas defects in T_H1 and T_H17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.

SUBMITTER: Tangye SG

PROVIDER: S-EPMC10500883 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

Dedicator of cytokinesis 8-deficient CD4<sup>+</sup> T cells are biased to a T<sub>H</sub>2 effector fate at the expense of T<sub>H</sub>1 and T<sub>H</sub>17 cells.

Tangye Stuart G SG Pillay Bethany B Randall Katrina L KL Avery Danielle T DT Phan Tri Giang TG Gray Paul P Ziegler John B JB Smart Joanne M JM Peake Jane J Arkwright Peter D PD Hambleton Sophie S Orange Jordan J Goodnow Christopher C CC Uzel Gulbu G Casanova Jean-Laurent JL Lugo Reyes Saul Oswaldo SO Freeman Alexandra F AF Su Helen C HC Ma Cindy S CS

The Journal of allergy and clinical immunology 20160820 3

<h4>Background</h4>Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4<sup>+</sup> T cells to disease pathogenesis in these patients has not been thoroughly investigated.<h4>Objective</h4>We sought to invest ...[more]

PMID: 27554822

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Project description:BackgroundMutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management.ObjectivesWe sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings.MethodsEighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations.ResultsDOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations.ConclusionsDOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

Dataset Information

Dedicator of cytokinesis 8-deficient CD4⁺ T cells are biased to a T_H2 effector fate at the expense of T_H1 and T_H17 cells.

Background

Objective

Methods

Results

Conclusion

Publications

Dedicator of cytokinesis 8-deficient CD4<sup>+</sup> T cells are biased to a T<sub>H</sub>2 effector fate at the expense of T<sub>H</sub>1 and T<sub>H</sub>17 cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Dedicator of cytokinesis 8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells.

Background

Objective

Methods

Results

Conclusion

Publications

Dedicator of cytokinesis 8-deficient CD4&lt;sup&gt;+&lt;/sup&gt; T cells are biased to a T&lt;sub&gt;H&lt;/sub&gt;2 effector fate at the expense of T&lt;sub&gt;H&lt;/sub&gt;1 and T&lt;sub&gt;H&lt;/sub&gt;17 cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dedicator of cytokinesis 8-deficient CD4⁺ T cells are biased to a T_H2 effector fate at the expense of T_H1 and T_H17 cells.

Dedicator of cytokinesis 8-deficient CD4<sup>+</sup> T cells are biased to a T<sub>H</sub>2 effector fate at the expense of T<sub>H</sub>1 and T<sub>H</sub>17 cells.