Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells

Abstract The systemic administration of keratinocyte growth factor (KGF) enhances T-cell lymphopoiesis in normal mice and mice that received a bone marrow transplant. KGF exerts protection to thymic stromal cells from cytoablative conditioning and graft-versus-host disease–induced injury. However, little is known regarding KGF's molecular and cellular mechanisms of action on thymic stromal cells. Here, we report that KGF induces in vivo a transient expansion of both mature and immature thymic epithelial cells (TECs) and promotes the differentiation of the latter type of cells. The increased TEC numbers return within 2 weeks to normal values and the microenvironment displays a normal architectural organization. Stromal changes initiate an expansion of immature thymocytes and permit regular T-cell development at an increased rate and for an extended period of time. KGF signaling in TECs activates both the p53 and NF-κB pathways and results in the transcription of several target genes necessary for TEC function and T-cell development, including bone morphogenetic protein 2 (BMP2), BMP4, Wnt5b, and Wnt10b. Signaling via the canonical BMP pathway is critical for the KGF effects. Taken together, these data provide new insights into the mechanism(s) of action of exogenous KGF on TEC function and thymopoiesis.

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Injury to the Thymic Niche for DN2/DN3 Developing T Cells Impairs Reconstitution.

Blood ◽

10.1182/blood.v108.11.68.68 ◽

2006 ◽

Vol 108 (11) ◽

pp. 68-68

Author(s):

Susan Prockop ◽

Sotiris Nikolopoulos ◽

Aaron Myers ◽

Filipo Giancotti ◽

Howard T. Petrie ◽

...

Keyword(s):

T Cell ◽

Stromal Cells ◽

De Novo ◽

T Cell Development ◽

Cell Development ◽

Cytotoxic Agents ◽

Thymic Epithelial Cells ◽

Laminin 5 ◽

Thymic Stroma ◽

Thymic Stromal Cells

Abstract Despite recovery of most hematopoietic functions, prolonged defects in generating functional T lymphocytes is a common occurrence after T cell depleted bone marrow transplant. While the mechanisms of these defects have not all been elucidated, contributing factors include age, T cell depletion of the graft, therapy with radiation and cytotoxic agents, and graft versus host disease (GvHD). We have designed an in vivo functional assessment of the ability of thymic stroma to support de novo T lymphocyte development. Mice deficient for the alpha chain of the IL-7 receptor (IL7Rα−/−) support robust thymic reconstitution after transplant of limited numbers of congenic precursors. We demonstrated that this capacity for reconstitution of immunodeficient strains depends on the paucity of specific endogenous precursors (DN3) cells in the IL7Rα−/− thymus and reflects the presence of functionally normal but empty stromal niches in this immunodeficient strain. We have proceeded to demonstrate that a variety of chemotherapeutic agents as well as aging, impair the ability of IL7Rα−/− thymic stroma to support de novo T cell development. Some agents allow donor chimerism in the thymus, but not rescue of the hypocellularity (eg cyclophosphamide) while others do not affect reconstitution (eg fludarabine). Multi-agent regimens have been administered and in some instances demonstrate an additive detrimental impact on thymic reconstitution. For several agents, damage has been localized to specific stromal niches by isolating changes in lymphoid subsets and stromal keratin expression. Decreased availability of the stromal niche for DN3 progenitors is associated with a decreased frequency of DN3s and an absolute block in recipient IL7Rα−/− T cell development. In addition, RNA from treated and untreated thymic stromal cells has been used to evaluate the gene expression pattern in thymic stroma of IL7Rα−/− mice treated with cytotoxic agents. In one example to be presented we find decreased thymic reconstitution in mice treated with Busulfan with sustained changes in stromal elements. These findings are consistent with sustained damage to thymic stromal cells. Among other changes, busulfan leads to decreased expression of laminin 5 by cortical thymic epithelial cells. The integrin heterodimerα6β4 is a binding partner for laminin 5 and is expressed uniformly by DN2 thymocytes. The significance of laminin 5/α6β4 signaling during T cell development was assessed using mice with a targeted mutation in the integrin β4 signaling domain. In these experiments mutant fetal liver was used to create hematopoietic chimeras and evaluate T cell development. Our studies provide insight into the nature of damage to thymic stroma by cytotoxic regimens and an understanding of the effect of this damage on subsequent immune reconstitution.

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Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration

Blood ◽

10.1182/blood-2005-07-2831 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2453-2460 ◽

Cited By ~ 139

Author(s):

Önder Alpdogan ◽

Vanessa M. Hubbard ◽

Odette M. Smith ◽

Neel Patel ◽

Sydney Lu ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Growth Factor ◽

Keratinocyte Growth Factor ◽

Critical Role ◽

T Cell Development ◽

Marrow Transplant ◽

Cell Development ◽

Allogeneic Bone ◽

Thymic Regeneration

AbstractKeratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF-/- mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF-/-, wildtype (WT), and KGF+/- mice were similar. However, KGF-/- mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF-/- recipients of syngeneic or allogeneic bone marrow transplant, but using KGF-/- mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. Finally, we found that administering KGF before bone marrow transplantation (BMT) resulted in enhanced thymopoiesis and peripheral T-cell numbers in middle-aged recipients of an allogeneic BM transplant. We conclude that KGF plays a critical role in postnatal thymic regeneration and may be useful in treating immune deficiency conditions. (Blood. 2006;107:2453-2460)

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Inborn errors of thymic stromal cell development and function

Seminars in Immunopathology ◽

10.1007/s00281-020-00826-9 ◽

2020 ◽

Author(s):

Alexandra Y. Kreins ◽

Stefano Maio ◽

Fatima Dhalla

Keyword(s):

T Cell ◽

Stromal Cells ◽

Stromal Cell ◽

Cell Development ◽

Thymic Epithelial Cells ◽

Inborn Errors ◽

Vascular Elements ◽

Thymus Tissue ◽

Thymic Stromal Cells ◽

Thymic Stromal Cell

AbstractAs the primary site for T cell development, the thymus is responsible for the production and selection of a functional, yet self-tolerant T cell repertoire. This critically depends on thymic stromal cells, derived from the pharyngeal apparatus during embryogenesis. Thymic epithelial cells, mesenchymal and vascular elements together form the unique and highly specialised microenvironment required to support all aspects of thymopoiesis and T cell central tolerance induction. Although rare, inborn errors of thymic stromal cells constitute a clinically important group of conditions because their immunological consequences, which include autoimmune disease and T cell immunodeficiency, can be life-threatening if unrecognised and untreated. In this review, we describe the molecular and environmental aetiologies of the thymic stromal cell defects known to cause disease in humans, placing particular emphasis on those with a propensity to cause thymic hypoplasia or aplasia and consequently severe congenital immunodeficiency. We discuss the principles underpinning their diagnosis and management, including the use of novel tools to aid in their identification and strategies for curative treatment, principally transplantation of allogeneic thymus tissue.

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Neoplastic thymic epithelial cells of human thymoma support T cell development from CD4− CD8− cells to CD4+ CD8+ cells in vitro

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.1998.00606.x ◽

1998 ◽

Vol 112 (3) ◽

pp. 419-426 ◽

Cited By ~ 19

Author(s):

Inoue ◽

Fujii ◽

Okumura ◽

Takeuchi ◽

Shiono ◽

...

Keyword(s):

T Cell ◽

Epithelial Cells ◽

T Cell Development ◽

Cell Development ◽

Thymic Epithelial Cells ◽

Cd8 Cells

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Non-Epithelial Stromal Cells in Thymus Development and Function

Frontiers in Immunology ◽

10.3389/fimmu.2021.634367 ◽

2021 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Kieran D. James ◽

William E. Jenkinson ◽

Graham Anderson

Keyword(s):

T Cell ◽

Stromal Cells ◽

T Cell Development ◽

Cell Development ◽

Thymic Epithelial Cells ◽

Developmental Origins ◽

Functional Classification ◽

Focus Attention ◽

Thymus Development ◽

And Function

The thymus supports T-cell developmentviaspecialized microenvironments that ensure a diverse, functional and self-tolerant T-cell population. These microenvironments are classically defined as distinct cortex and medulla regions that each contain specialized subsets of stromal cells. Extensive research on thymic epithelial cells (TEC) within the cortex and medulla has defined their essential roles during T-cell development. Significantly, there are additional non-epithelial stromal cells (NES) that exist alongside TEC within thymic microenvironments, including multiple subsets of mesenchymal and endothelial cells. In contrast to our current understanding of TEC biology, the developmental origins, lineage relationships, and functional properties, of NES remain poorly understood. However, experimental evidence suggests these cells are important for thymus function by either directly influencing T-cell development, or by indirectly regulating TEC development and/or function. Here, we focus attention on the contribution of NES to thymic microenvironments, including their phenotypic identification and functional classification, and explore their impact on thymus function.

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Damage to Aging Thymic Stroma and De Novo T Cell Development.

Blood ◽

10.1182/blood.v110.11.3264.3264 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3264-3264

Author(s):

Susan Prockop ◽

Ana Beesen ◽

Aaron Myers ◽

Richard J. O’Reilly

Keyword(s):

At Risk ◽

T Cell ◽

Stromal Cells ◽

De Novo ◽

T Cell Development ◽

Cell Development ◽

Age Related ◽

Thymic Stroma ◽

Thymic Stromal Cells ◽

T Lymphopoiesis

Abstract Successful T lymphopoiesis is essential for maintaining resistance to infection, mediating graft versus tumor activity, and as a platform for some immune based therapies. Among the most profound age-related change affecting the hemopoietic system is involution of the thymus and a decline in T cell production. Coordinated interaction of marrow-derived lymphoid progenitors with thymic stromal cells is required for successful de novo T lymphopoiesis. Current models of thymic involution indicate that aging alters the capacity of thymic stromal cells to support this de novo T cell lymphopoiesis. Loss of specific sets of thymic stromal cells, or loss of specific lympho-stromal signaling interactions may partially explain age-based impaired T cell reconstitution. Prior models examining the potential to reconstitute the aged thymus have been conducted either in vitro or in cyto-reduced hosts, and thus largely risk confounding cytotoxic damage with age-related damage. We have established an in vivo functional assessment of the ability of thymic stroma to support de novo T lymphocyte development. In the absence of radiation or chemotherapy this system supports robust thymic reconstitution after transplantation of limited numbers of T cell depleted wild type precursors. We have previously demonstrated that the capacity for reconstitution in this model system depends on the presence of normal, but empty, stromal niches. Using this model we have demonstrated that a variety of chemotherapeutic agents damage the thymic stroma and impair robust reconstitution. We now present data demonstrating that with increasing age reconstitution becomes less robust. Thus in mice older than 16 months unlike in those younger than twelve months, donor derived T lymphocytes can be identified, but the absolute cellularity of the thymus does not increase after transplant. In addition, we demonstrate that there are agent specific defects in the stromal compartments of treated aged mice. We have proceeded to identify a subset of agents (including split dose irradiation) that impair reconstitution in aged recipients but do not do so in the young. Thus while reconstitution of the thymus of young mice subjected to hyperfractionated total body irradiation declines 28 +/− 3% that of old mice treated in the same manner declines 91 +/− 6%. This last finding has enabled us to identify specific “at risk” stromal populations that normally appear to support the DN2 to DN3 transition in T lymphopoiesis. In a series of experiments designed to ask whether these at risk stromal populations can be protected from injury we identify agent specific differences in mechanisms of injury. It is anticipated that results from these investigations will augment our understanding of lympho-stromal interactions crucial to normal intra-thymic T cell development.

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