دكتوراه
الطب والخدمات الصحية
University of Birmingham
مجال التميز | تميز دراسي وبحثي |
البحوث المنشورة |
|
البحث (1): | |
عنوان البحث: | Generation and Regeneration of Thymic Epithelial Cells |
رابط إلى البحث: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.00858/full |
تاريخ النشر: | 07/05/2020 |
موجز عن البحث: | The thymus is unique in its ability to support the maturation of phenotypically and functionally distinct T cell sub-lineages. Through its combined production of MHC-restricted conventional CD4+ and CD8+, and Foxp3+ regulatory T cells, as well as non-conventional CD1d-restricted iNKT cells and invariant γδT cells, the thymus represents an important orchestrator of immune system development and control. It is now clear that thymus function is largely determined by the availability of stromal microenvironments. These specialized areas emerge during thymus organogenesis and are maintained throughout life. They are formed from both epithelial and mesenchymal components, and collectively they support a stepwise program of thymocyte development. Of these stromal cells, cortical, and medullary thymic epithelial cells represent functional components of thymic microenvironments in both the cortex and medulla. Importantly, a key feature of thymus function is that levels of T cell production are not constant throughout life. Here, multiple physiological factors including aging, stress and pregnancy can have either short- or long-term detrimental impact on rates of thymus function. Here, we summarize our current understanding of the development and function of thymic epithelial cells, and relate this to strategies to protect and/or restore thymic epithelial cell function for therapeutic benefit. |
المؤتمرات العلمية |
|
المؤتمر (1): | |
عنوان المؤتمر: | British Society for Immunology |
تاريخ الإنعقاد: | 01/12/2020 |
مكان الإنعقاد: | UK |
طبيعة المشاركة: | Oral Presentation |
عنوان المشاركة: | Failures In the Recovery of Thymus Medulla Function Lead To Loss of T-cell Tolerance Following Bone Marrow Transplantation |
ملخص المشاركة: | Bone marrow transplantation (BMT) is commonly used for the treatment of haemopoietic malignancies. Following transplant, the restoration of thymus function is critical for therapeutic immune system recovery, which involves intrathymic abT-cell production from transfused donor progenitors. However, these clinical interventions require ablative therapies and immunosuppression that can limit thymus function and create life-threatening side effects including secondary immunodeficiency and autoimmunity. While thymus damage caused by pre-transplant ablative therapies delays T-cell reconstitution, the ability of the thymus to impose central tolerance during phases of recovery is poorly understood. Here, we used an MHC-matched congenic mouse model of BMT and studied the recovery of the thymic microenvironments with relation to immune reconstitution and the generation of new T cells. Importantly, our analysis shows while cTEC remained relatively constant, we saw a rapid and sustained decline in mTEC following BMT. Strikingly our analysis shows rapid recovery of conventional CD4+ thymocytes that led to an accumulation of this cell type post BMT as early as d21. However, development of medulla-dependent Foxp3+ T-Reg showed delayed kinetics and did not reach normal levels by d28 post-transplant. Moreover, analysis of negative selection to endogenously expressed MMTV self-antigens was impaired in BMT mice, with mature T-cells expressing ‘forbidden’ TCRb chains detectable in the thymus and periphery. Finally, transfer of CD4+ thymocytes from BMT mice into nude hosts generated autoimmune symptoms including lymphocytic infiltrates and auto-antibodies. Collectively, our findings suggest that following BMT, thymus function is initially skewed towards T-cell production and not T-cell tolerance. This can be explained by the slow recovery of medullary microenvironments, which points towards the importance of therapeutic strategies that selectively boost medulla recovery post-BMT to ensure self-tolerant T-cell reconstitution. |
المؤتمر (2): | |
عنوان المؤتمر: | 5th European Congress of Immunology – ECI 2018 – |
تاريخ الإنعقاد: | 02/09/2018 |
مكان الإنعقاد: | Amsterdam, The Netherlands |
طبيعة المشاركة: | Poster Presentation |
عنوان المشاركة: | Differential Recovery of Intrathymic Microenvironments That Follows 5 Thymus Damage Results In Qualitative Changes in T-cell Reconstitution |
ملخص المشاركة: | Following ablative therapies used for cancer treatment, damage to the thymus disrupts it ability to support T-cell development. This results in delayed T-cell reconstitution and a period of immunodeficiency that leaves patients susceptible to potentially fatal infections. Thus, examining mechanisms that control thymus regeneration, and identifying new approaches to boost thymus recovery, are important in devising new therapeutic strategies to improve immune reconstitution. We have used sub-lethal irradiation (SLI) in a mouse model of thymic injury and performed systematic examination of the recovery of both thymocytes and the thymic microenvironment. Following SLI, we find the generation of CD4+CD8+ thymocytes and their CD4+ and CD8+ progeny occurs in two distinct waves. Analysis of early thymic progenitors indicates that while an initial and transient wave of recovery occurs via a radioresistant intrathymic progenitor, a second sustained wave occurs via thymus entry of bone marrow progenitors. Surprisingly, concurrent analysis of the thymic microenvironment indicates cortical thymic epithelial cell numbers remain constant, suggesting they are radioresistant and available to support thymocyte development. In contrast, medullary thymic epithelial cells and dendritic cells are depleted following damage. Consistent with this, recovery of medulla-dependent Foxp3+ regulatory T-cells occurs after the generation of conventional CD4+ thymocytes. In summary, our findings suggest that following damage, distinct thymic areas show differential recovery kinetics that impact upon the quality of new T-cell production. Ongoing studies are examining whether known regulators of thymus recovery, including KGF and LTbR stimulation, can restore medullary microenvironments to ensure balanced recovery of T-cell development. |