رسالة جامعية
EXPRESSION PATTERNS AND ROLES OF THE IKAROS FAMILY OF TRANSCRIPTION FACTORS IN HUMAN REGULATORY T CELL DEVELOPMENT AND FUNCTION.
| العنوان: | EXPRESSION PATTERNS AND ROLES OF THE IKAROS FAMILY OF TRANSCRIPTION FACTORS IN HUMAN REGULATORY T CELL DEVELOPMENT AND FUNCTION. |
|---|---|
| المؤلفون: | Seng, Amara |
| المساهمون: | Markiewicz, Mary A, Benedict, Stephen H, Fields, Timothy A, Fischer, Ryan T, Lutkenhaus, Joe |
| بيانات النشر: | University of Kansas |
| سنة النشر: | 2019 |
| المجموعة: | The University of Kansas: KU ScholarWorks |
| مصطلحات موضوعية: | Immunology, FOXP3, graft versus host disease, Helios, Ikaros, regulatory T cells, Treg |
| الوصف: | Regulatory T cells (Tregs) are a small subset of immune cells that are responsible for downregulating the immune response and maintaining immune tolerance. Tregs are generally defined by a high expression of the transcription factor FOXP3. Dysfunction of Treg activity or number is the basis of many inflammatory diseases. Thus, there has been much research on understanding Treg development in the thymus and activity in the periphery and Tregs are being studied as a potential cellular therapy. One form of Treg therapy is generating engineered Tregs (eTregs), which involves expressing Treg genes in conventional T cells through retroviral or lentiviral transduction. The work described here investigates the role of the Ikaros family of transcription factors in eTreg function and thymic Treg development. The Ikaros family members, namely Helios and Eos, have been implicated as critical mediators of Treg induction and function. In the first study, we hypothesized that ectopic expression of Helios with FOXP3 is required for optimal engineered Treg immunosuppression. In the second study, we hypothesized that Ikaros family member expression correlates with Treg marker expression and defines points of Treg lineage commitment within CD4+ mature single positive (MSP) Tregs in the thymus. In the first study, we generated eTregs by retrovirally transducing total human T cells with combinations of FOXP3, Helios (Hel-FL) and Δ3B Helios (Hel-Δ3B), a relevant splice variant of Helios. FOXP3+Hel-FL eTregs were the only eTregs able to delay disease in a xenogenic Graft versus Host Disease model. In vitro, FOXP3+Hel-FL CD4+ eTregs suppressed T cell proliferation more effectively than FOXP3 and FOXP3+Hel-Δ3B CD4+ eTregs. However, both FOXP3+Hel-FL CD8+ eTregs and FOXP3+Hel-Δ3B CD8+ eTregs were more effective than FOXP3 alone. RNA Sequencing of the CD4+ and CD8+ eTregs demonstrated that the addition of Hel-FL to FOXP3 in eTregs changed gene expression in cellular pathways and the Treg signature compared to FOXP3 alone or FOXP3+Hel-Δ3B. ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| وصف الملف: | 159 pages; application/pdf; application/vnd.openxmlformats-officedocument.spreadsheetml.sheet |
| اللغة: | English |
| العلاقة: | http://dissertations.umi.com/ku:16497Test; http://hdl.handle.net/1808/30134Test; orcid:0000-0001-7077-5969 |
| الإتاحة: | http://hdl.handle.net/1808/30134Test http://dissertations.umi.com/ku:16497Test |
| حقوق: | Copyright held by the author. ; openAccess |
| رقم الانضمام: | edsbas.B2AE6C35 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |