Migration-induced cell shattering due to DOCK8 deficiency causes a type 2–biased helper T cell response

Schneider, Charles L.; Shen, Connie; Gopal, Angelica A.; Douglas, Todd; Forestell, Benjamin; Kauffman, Keith D.; Rogers, Dakota; Artusa, Patricio; Jing, Huie; Freeman, Alexandra F.; Barber, Daniel L.; King, Irah L.; Saleh, Maya; Wiseman, Paul W.; Su, Helen C.; Mandl, Judith N.

doi:10.1038/s41590-020-0795-1

Cited by 28 publications

(27 citation statements)

References 61 publications

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“…Spleen and peripheral lymph nodes (inguinal, axillary, brachial, superficial cervical, and mesenteric) were isolated as previously described (Schneider et al, 2020). For experiments where naïve CD4 + T cells were rested in culture, cells (either total or sorted, as specified) were kept in complete RPMI (10% FBS, 1% L-glutamine, 1% pen/strep, 1% HEPES buffer, 1% Sodium Pyruvate, 1% non-essential Amino Acids, 0.1% 2-mercapto-ethanol 1000X solution) supplemented with IL-7 (10 ng/mL, Biolegend).…”

Section: Lymphocyte Isolation Resting Activation and Restimulationmentioning

confidence: 99%

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Pre-existing chromatin accessibility and gene expression differences among naïve CD4⁺T cells influence effector potential

Rogers

Sood

Wang

et al. 2021

Preprint

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SummaryCD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probed the heterogeneity present among naïve CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and epigenetic differences. Using single-cell RNA sequencing, we showed that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a read-out of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naïve CD4+ T cells impact follicular helper cell (TFH) versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naïve CD4 T cell chromatin landscapes that ultimately shape their effector potential.

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Section: Lymphocyte Isolation Resting Activation and Restimulationmentioning

confidence: 99%

“…To activate T cells, sorted cells or total splenocytes were cultured in complete RPMI in flat-bottomed 96-well plates coated with a-CD3 and a-CD28 (Invitrogen; both at 3µg/mL). Restimulation of splenocytes for cytokine production was performed as previously described (Schneider et al, 2020).…”

Section: Lymphocyte Isolation Resting Activation and Restimulationmentioning

confidence: 99%

Pre-existing chromatin accessibility and gene expression differences among naïve CD4⁺T cells influence effector potential

Rogers

Sood

Wang

et al. 2021

Preprint

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“…What is the relevance of the findings of Schneider et al 6 to the development of a T H 2-dominated allergic response in DOCK8-deficient patients to food and inhaled allergens? This question is important for allergists because DOCK8-deficient patients mount exaggerated T H 2 responses to allergens that elicit a T H 2 response in atopic individuals.…”

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confidence: 99%

“…4,5 Both DOCK8-deficient T cells and dendritic cells (DCs) undergo cell shattering or cytothripsis when moving in vitro through collagen matrices. 4,6 Despite varied defects observed in DOCK8-deficient immune cells, DOCK8-deficient patients and mice are still able to mount significant inflammatory responses to certain stimuli, albeit often with exaggerated type 2 skewing.…”

mentioning

confidence: 99%

“…Over 10 years after identification of DOCK8 deficiency as a major cause of autosomal-recessive hyper-IgE syndrome, much is still unknown regarding the molecular mechanisms driving this disease. Although abnormalities in the shape, migration, and survival of DOCK8-deficient immune cells have been known for some time, the report by Schneider et al 6 links the increased susceptibility to migration-induced cell death of a specific population of immune cells with T H 2 skewing of the immune response in DOCK8 deficiency. This intriguing observation suggests a novel mechanism for the development of allergic disease and also invites a number of questions.…”

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confidence: 99%

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Macabre TH2 skewing in DOCK8 deficiency

Janssen

Wilkie

2021

Journal of Allergy and Clinical Immunology

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Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4⁺ T cells

Jiang,

Zhao,

et al. 2024

MedComm

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Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA‐bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF‐1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8‐deficient patients.

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Migration-induced cell shattering due to DOCK8 deficiency causes a type 2–biased helper T cell response

Cited by 28 publications

References 61 publications

Pre-existing chromatin accessibility and gene expression differences among naïve CD4⁺T cells influence effector potential

Pre-existing chromatin accessibility and gene expression differences among naïve CD4⁺T cells influence effector potential

Macabre TH2 skewing in DOCK8 deficiency

Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4⁺ T cells

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Migration-induced cell shattering due to DOCK8 deficiency causes a type 2–biased helper T cell response

Cited by 28 publications

References 61 publications

Pre-existing chromatin accessibility and gene expression differences among naïve CD4+T cells influence effector potential

Pre-existing chromatin accessibility and gene expression differences among naïve CD4+T cells influence effector potential

Macabre TH2 skewing in DOCK8 deficiency

Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4+ T cells

Contact Info

Product

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Pre-existing chromatin accessibility and gene expression differences among naïve CD4⁺T cells influence effector potential

Pre-existing chromatin accessibility and gene expression differences among naïve CD4⁺T cells influence effector potential

Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4⁺ T cells