Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome
Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanis...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-04-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00753/full |
| _version_ | 1818421005775798272 |
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| author | Timothy J. Thauland Laurence Pellerin Robert S. Ohgami Rosa Bacchetta Manish J. Butte |
| author_facet | Timothy J. Thauland Laurence Pellerin Robert S. Ohgami Rosa Bacchetta Manish J. Butte |
| author_sort | Timothy J. Thauland |
| collection | DOAJ |
| description | Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4+ T cells to a T follicular helper (TFH) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote TFH differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that TFH should be monitored in APDS patients. |
| first_indexed | 2024-12-14T13:03:29Z |
| format | Article |
| id | doaj.art-76a5fb0566f14f57964c35dcc41b6e8b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T13:03:29Z |
| publishDate | 2019-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-76a5fb0566f14f57964c35dcc41b6e8b2022-12-21T23:00:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-04-011010.3389/fimmu.2019.00753449293Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta SyndromeTimothy J. Thauland0Laurence Pellerin1Robert S. Ohgami2Rosa Bacchetta3Manish J. Butte4Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United StatesDivision of Pediatric Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, United StatesDepartment of Pathology, Stanford University, Stanford, CA, United StatesDivision of Pediatric Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, United StatesDivision of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United StatesGain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4+ T cells to a T follicular helper (TFH) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote TFH differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that TFH should be monitored in APDS patients.https://www.frontiersin.org/article/10.3389/fimmu.2019.00753/fullprimary immunodeficiencyactivated PI3K delta syndrome (APDS)PI3KT follicular helper cellsosteopontin |
| spellingShingle | Timothy J. Thauland Laurence Pellerin Robert S. Ohgami Rosa Bacchetta Manish J. Butte Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome Frontiers in Immunology primary immunodeficiency activated PI3K delta syndrome (APDS) PI3K T follicular helper cells osteopontin |
| title | Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome |
| title_full | Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome |
| title_fullStr | Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome |
| title_full_unstemmed | Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome |
| title_short | Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome |
| title_sort | case study mechanism for increased follicular helper t cell development in activated pi3k delta syndrome |
| topic | primary immunodeficiency activated PI3K delta syndrome (APDS) PI3K T follicular helper cells osteopontin |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00753/full |
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