Biomedical subjects

Jason Gill

Publications and source records attributed to Jason Gill.

7 recordsLinked to original sources

PubMed2007

Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation.

Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-gamma, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.

Acute Disease↗

PubMed2006

Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling.

A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the basis for establishing central tolerance.

Animals↗

PubMed2006

Cellular and molecular events during early thymus development.

The thymic stromal compartment consists of several cell types that collectively enable the attraction, survival, expansion, migration, and differentiation of T-cell precursors. The thymic epithelial cells constitute the most abundant cell type of the thymic microenvironment and can be differentiated into morphologically, phenotypically, and functionally separate subpopulations of the postnatal thymus. All thymic epithelial cells are derived from the endodermal lining of the third pharyngeal pouch. Very soon after the formation of a thymus primordium and prior to its vascularization, thymic epithelial cells orchestrate the first steps of intrathymic T-cell development, including the attraction of lymphoid precursor cells to the thymic microenvironment. The correct segmentation of pharyngeal epithelial cells and their subsequent crosstalk with cells in the pharyngeal arches are critical prerequisites for the formation of a thymus anlage. Mutations in several transcription factors and their target genes have been informative to detail some of the complex mechanisms that control the development of the thymus anlage. This review highlights recent findings related to the genetic control of early thymus organogenesis and provides insight into the molecular basis by which lymphocyte precursors are attracted to the thymus.

Animals↗

PubMed2003

Thymic generation and regeneration.

The thymus is a complex epithelial organ in which thymocyte development is dependent upon the sequential contribution of morphologically and phenotypically distinct stromal cell compartments. It is these microenvironments that provide the unique combination of cellular interactions, cytokines, and chemokines to induce thymocyte precursors to undergo a differentiation program that leads to the generation of functional T cells. Despite the indispensable role of thymic epithelium in the generation of T cells, the mediators of this process and the differentiation pathway undertaken by the primordial thymic epithelial cells are not well defined. There is a lack of lineage-specific cell-surface-associated markers, which are needed to characterize putative thymic epithelial stem cell populations. This review explores the role of thymic stromal cells in T-cell development and thymic organogenesis, as well as the molecular signals that contribute to the growth and expansion of primordial thymic epithelial cells. It highlights recent advances in these areas, which have allowed for a lineage relationship amongst thymic epithelial cell subsets to be proposed. While many fundamental questions remain to be addressed, collectively these works have broadened our understanding of how the thymic epithelium becomes specialized in the ability to support thymocyte differentiation. They should also facilitate the development of novel, rationally based therapeutic strategies for the regeneration and manipulation of thymic function in the treatment of many clinical conditions in which defective T cells have an important etiological role.

Animals↗

PubMed2002

Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice.

T cell development and selection require the fully mature and diverse epithelial microenvironment of the thymus. Acquisition of these characteristics is dependent on expression of the forkhead (also known as winged-helix) transcription factor FoxN1, as a lack of functional FoxN1 results in aberrant epithelial morphogenesis and an inability to attract lymphoid precursors to the thymus primordium. However, the transcriptional control of Foxn1 expression has not been elucidated. Here we report that secreted Wnt glycoproteins, expressed by thymic epithelial cells and thymocytes, regulate epithelial Foxn1 expression in both autocrine and paracrine fashions. Wnt molecules therefore provide regulatory signals critical for thymic function.

3T3 Cells↗

PubMed2002

Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells.

The epithelial component of the thymic microenvironment is indispensable for the generation of T lymphocytes. Although the heterogeneity of this epithelium is well documented, little is known about precursor-progeny relationships between distinct thymic epithelial lineages. Here we characterized a thymic epithelial cell subpopulation identified by the cell surface glycoprotein MTS24. These cells contained epithelial progenitor cells that were competent and sufficient to fully reconstitute the complex thymic epithelial microenvironment that supported normal T cell development.

Animals↗

PubMed2002

Thymic regeneration: teaching an old immune system new tricks.

Recent studies in mice and humans show that the importance of the thymus extends well beyond the initial seeding of the peripheral T-cell pool. Although peripheral homeostasis can maintain T-cell numbers, the thymus is the major, if not the exclusive, source of new T-cell specificities. With age, thymus atrophy dramatically reduces the export of new T cells and predisposes an individual to impaired T-cell function, reduced T-cell immunity, and increased autoimmunity. Thymus atrophy is also the primary obstacle to restoration of the T-cell pool in the aftermath of HIV treatment or lymphoablative therapies. Here, we review thymus T-cell production, with particular attention to the factors that influence thymocyte export, and examine the impact that recent thymic emigrants have on the peripheral pool. In the future, thymic regeneration might become a feasible and potentially powerful approach to rejuvenating a depleted peripheral T-cell pool.

Aging↗