Biomedical subjects

Alberto Varas

Publications and source records attributed to Alberto Varas.

11 recordsLinked to original sources

PubMed2005

Sonic hedgehog is produced by follicular dendritic cells and protects germinal center B cells from apoptosis.

The Hedgehog (Hh) signaling pathway is involved in the development of many tissues during embryogenesis, but has also been described to function in adult self-renewing tissues. In the immune system, Sonic Hedgehog (Shh) regulates intrathymic T cell development and modulates the effector functions of peripheral CD4(+) T cells. In this study we investigate whether Shh signaling is involved in peripheral B cell differentiation in mice. Shh is produced by follicular dendritic cells, mainly in germinal centers (GCs), and GC B cells express both components of the Hh receptor, Patched and Smoothened. Blockade of the Hh signaling pathway reduces the survival, and consequently the proliferation and Ab secretion, of GC B cells. Furthermore, Shh rescues GC B cells from apoptosis induced by Fas ligation. Taken together, our data suggest that Shh is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in GC B cells.

Animals↗

PubMed2004

Sonic hedgehog regulates early human thymocyte differentiation by counteracting the IL-7-induced development of CD34+ precursor cells.

The Hedgehog (Hh) family of signaling molecules normally functions in the development of numerous tissues by regulating cellular differentiation and proliferation. Recent results have demonstrated that the different components of the Hh signaling pathway are expressed in the human thymus. In this study, we investigate the potential role of Sonic hedgehog (Shh) in human intrathymic T cell maturation. Results show that the expression of the two components of the Hh receptor, Patched and Smoothened, is mostly restricted to CD34+ precursor cells that are committing to the T cell lineage. Shh significantly increased the viability of CD34+ T cell precursors modulating bcl-2 and bax protein expression, and also inhibited their proliferation. The treatment of chimeric human-mouse fetal thymus organ cultures with Shh resulted in an arrested thymocyte differentiation and an accumulation of CD34+ progenitor cells. This effect was mainly attributed to the ability of Shh to counteract the IL-7-induced proliferation and differentiation of CD34+ cells. Shh down-regulated in the precursor cell population the expression of IL-7R as well as stromal-derived factor-1 chemokine receptor, CXCR4, and inhibited IL-7-dependent STAT5 phosphorylation. Therefore, Shh may function as a maintenance factor for intrathymic CD34+ precursor cells.

Antigens, CD34↗

PubMed2004

Reduced thymocyte development in sonic hedgehog knockout embryos.

The Hedgehog family of secreted intercellular signaling molecules are regulators of patterning and organogenesis during animal development. In this study we provide genetic evidence that Sonic Hedgehog (Shh) has a role in the control of murine T cell development. Analysis of Shh(-/-) mouse embryos revealed that Shh regulates fetal thymus cellularity and thymocyte differentiation. Shh is necessary for expansion of CD4(-)CD8(-) double-negative (DN) thymocytes and for efficient transition from the earliest CD44(+)CD25(-) DN population to the subsequent CD44(+)CD25(+) DN population and from DN to CD4(+)CD8(+) double-positive cells.

Animals↗

PubMed2003

Age-dependent changes in thymic macrophages and dendritic cells.

Aging is characterized by the decline and deregulation of several physiological systems, especially the immune system. The involution of the thymus gland has been identified as one of the key events that precedes the age-related decline in immune function. Whereas the decrease in thymocyte numbers and in the thymic output during thymus atrophy has been analyzed by various authors, very little information is available about the age-associated modifications in thymic macrophages and dendritic cells. Here we present evidence that these thymic stromal cell components are only slightly affected by age.

Aging↗

PubMed2003

The role of morphogens in T-cell development.

The Hedgehog (Hh) and Wnt family proteins, and the bone morphogenetic proteins (BMPs) 2 and 4, act as morphogens during vertebrate embryogenesis and organogenesis by regulating patterning and cell fate. They have recently been found to have a role in regulating cell fate and determination in self-renewing tissues in adults, such as the immune system and haematopoietic system. This Review presents studies on the role of Sonic Hh (Shh), Wnts and BMP2/4 in the regulation of thymocyte development. Shh and BMP2/4 act as negative regulators of thymocyte development. By contrast, Wnt signalling, through beta-catenin, has a positive role in the control of T-cell development, such that an absence or reduction in the Wnt signal leads to a reduction in cell number and cell proliferation rate and differentiation to the CD4+CD8+ double-positive stage.

Animals↗

PubMed2003

Expression of hedgehog proteins in the human thymus.

The Hedgehog (Hh) family of secreted proteins includes intercellular signaling molecules that specify cell fate and patterning during the development of many tissues. In this study we show that the different components of the Hh signaling pathway are expressed in human thymus. The three mammalian Hh proteins, Sonic (Shh), Indian (Ihh), and Desert (Dhh) hedgehog, are produced by thymic epithelial cells. Shh-expressing epithelial cells are restricted to the thymic subcapsula and medulla, whereas Ihh- and Dhh-producing epithelial cells are distributed throughout the thymus. The requisite Hh receptors, Patched 1(Ptc1) and Smoothened (Smo), and the Gli transcription factors are expressed by thymocytes and also by epithelial cells. Ptc1 is expressed in most thymocyte subsets, whereas Smo expression is mainly associated with immature thymocytes. The isoform of the Ptc receptor, Ptc2, is expressed only by intrathymic progenitor cells and epithelial cells. Other Hh-binding proteins with modulating functions, such as Hedgehog-interacting protein (Hip) and growth arrest-specific gene-1 (Gas-1), are also expressed in human thymus. Our study shows that the intrathymic expression pattern of the Hh signaling pathway components is complex and suggests that Hh proteins may regulate human thymocyte differentiation from the earliest developmental stages, as well as thymic epithelial cell function.

Cell Line↗

PubMed2002

Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation.

Bone morphogenetic protein (BMP)2 and BMP4 are involved in the development of many tissues. In this study, we show that BMP2/4 signaling is involved in thymocyte development. Our data suggest that termination of BMP2/4 signaling is necessary for differentiation of CD44(+)CD25(-)CD4(-)CD8(-) double negative (DN) cells along the T cell lineage. BMP2 and BMP4 are produced by the thymic stroma and the requisite BMP receptor molecules (BMPR-1A, BMPR-1B, BMPR-II), and signal transduction molecules (Smad-1, -5, -8, and -4) are expressed by DN thymocytes. BMP4 inhibits thymocyte proliferation, enhances thymocyte survival, and arrests thymocyte differentiation at the CD44(+)CD25(-) DN stage, before T cell lineage commitment. Neutralization of endogenous BMP2 and BMP4 by treatment with the antagonist Noggin promotes and accelerates thymocyte differentiation, increasing the expression of CD2 and the proportion of CD44(-)CD25(-) DN cells and CD4(+)CD8(+) double-positive cells. Our study suggests that the BMP2/4 pathway may function in thymic homeostasis by regulating T cell lineage commitment and differentiation.

Activin Receptors, Type I↗

PubMed2002

Expression and function of the Eph A receptors and their ligands ephrins A in the rat thymus.

Thymus development and function are dependent on the definition of different and graded microenvironments that provide the maturing T cell with the different signals that drive its maturation to a functional T lymphocyte. In these processes, cell-cell interactions, cell migration, and positioning are clues for the correct functioning of the organ. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, has been implicated in all these processes by regulating cytoskeleton and adhesion functioning, but a systemic analysis of their presence and possible functional role in thymus has not yet been conducted. In this regard, the current study combines different experimental approaches for analyzing the expression of four members of the Eph A family and their ligands, ephrins A, in the embryonic and adult rat thymus. The patterns of Eph and ephrin expression in the distinct thymic regions were different but overlapping. In general, the studied Eph A were expressed on thymic epithelial cells, whereas ephrins A seem to be more restricted to thymocytes, although Eph A1 and ephrin A1 are expressed on both cell types. Furthermore, the supply of either Eph A-Fc or ephrin A-Fc fusion proteins to fetal thymus organ cultures interferes with T cell development, suggesting an important role for this family of proteins in the cell mechanisms that drive intrathymic T cell development.

Animals↗

PubMed2002

Rat peripheral CD4+CD8+ T lymphocytes are partially immunocompetent thymus-derived cells that undergo post-thymic maturation to become functionally mature CD4+ T lymphocytes.

CD4+CD8+ double-positive (DP) T cells represent a minor subpopulation of T lymphocytes found in the periphery of adult rats. In this study, we show that peripheral DP T cells appear among the first T cells that colonize the peripheral lymphoid organs during fetal life, and represent approximately 40% of peripheral T cells during the perinatal period. Later their proportion decreases to reach the low values seen in adulthood. Most DP T cells are small size lymphocytes that do not exhibit an activated phenotype, and their proliferative rate is similar to that of the other peripheral T cell subpopulations. Only 30-40% of DP T cells expresses CD8beta chain, the remaining cells expressing CD8alphaalpha homodimers. However, both DP T cell subsets have an intrathymic origin since they appear in the recent thymic emigrant population after injection of FITC intrathymically. Functionally, although DP T cells are resistant to undergo apoptosis in response to glucocorticoids, they show poor proliferative responses upon CD3/TCR stimulation due to their inability to produce IL-2. A fraction of DP T cells are not actively synthesizing the CD8 coreceptor, and they gradually differentiate to the CD4 cell lineage in reaggregation cultures. Transfer of DP T lymphocytes into thymectomized SCID mice demonstrates that these cells undergo post-thymic maturation in the peripheral lymphoid organs and that their CD4 cell progeny is fully immunocompetent, as judged by its ability to survive and expand in peripheral lymphoid organs, to proliferate in response to CD3 ligation, and to produce IL-2 upon stimulation.

Aging↗

PubMed2002

Stromal cell-derived factor 1/CXCR4 signaling is critical for early human T-cell development.

The present study investigated the potential role of stromal cell-derived factor 1 (SDF-1) in human intrathymic T-cell differentiation. Results show that SDF-1 is produced by human thymic epithelial cells from the subcapsular and medullary areas, and its receptor, CXCR4, is up-regulated on CD34(+) precursor cells committed to the T-cell lineage. Chimeric human-mouse fetal thymus organ culture (FTOC) seeded with purified CD34(+) thymic progenitors and treated with neutralizing antibodies against SDF-1 or CXCR4 showed a significant reduction of the number of human thymocytes and an arrested thymocyte differentiation in the transition between CD34(+) precursor cells and CD4(+) immature thymocytes. SDF-1-treated FTOC showed an increase of human thymocyte numbers, mainly affecting the most immature subpopulations. Moreover, these results suggest that CXCR4/SDF-1 signaling is not critical for the CD34(+) cell precursor recruitment to the thymus. On the other hand, SDF-1 significantly increased the viability of CD34(+) T-cell precursors modulating the expression of BCL-2 and BAX genes, and stimulated the proliferation of CD34(+) thymic precursor cells, particularly in synergy with interleukin 7 (IL-7), but not with other cytokines, such as stem cell factor or flt3-ligand. Accordingly, only IL-7 was able to up-regulate CXCR4 expression on CD34(+) thymic progenitors. In addition, deprivation of SDF-1 partially inhibited human thymocyte expansion induced by IL-7 in human-mouse FTOC. This study indicates that SDF-1/CXCR4 signaling is required for the survival, expansion, and subsequent differentiation of human early thymocytes and identifies a new mechanism by which IL-7 mediates its effects on human thymopoiesis.

Animals↗

PubMed2002

Diacylglycerol kinase alpha activity promotes survival of CD4+ 8+ double positive cells during thymocyte development.

The diacylglycerol kinases (DGK) form a family of isoenzymes that catalyse the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), both powerful second messengers in the cell. DGKalpha is expressed in brain, peripheral T cells and thymocytes and has been shown to translocate to the nuclear matrix upon T-cell receptor (TCR) engagement. Here, we show that high level expression of DGKalpha is induced following a signal transmitted through the pre-TCR and the protein tyrosine kinase, lck. Activity of DGKalpha contributes to survival in CD4+ 8+ (DP) thymocytes as pharmacological inhibition of DGK activity results in death of this cell population both in cell suspension and thymic explants. DGKalpha promotes survival in these thymocytes through a Bcl-regulated pathway. A consequence of inhibition of DGKalpha is the specific down-regulation of Bcl-xl, whereas in transgenic mice that over-express Bcl-2, death induced by the inhibitor is partially blocked. Thus we report a novel activity of DGKalpha in survival of thymocytes immediately after entry into the DP stage in development.

Animals↗