Biomedical subjects

Alena M Gallegos

Publications and source records attributed to Alena M Gallegos.

4 recordsLinked to original sources

PubMed2006

Central tolerance: good but imperfect.

T-cell development is a highly coordinated process that depends on interactions between thymocytes, thymic epithelium, and bone marrow (BM)-derived dendritic cells (DCs). Before entering the peripheral T-cell pool, thymocytes are subject to negative selection, a process that eliminates (or deletes) T cells with high affinity toward self-antigens and therefore promotes self-tolerance. These self-antigens include those that are broadly expressed ubiquitous antigens and those whose expression is restricted to a few tissues, tissue-specific antigens (TSAs). Expression of TSAs in the thymus is mostly a property of medullary thymic epithelial cells (mTECs), and because these cells may be less capable than BM-derived DCs at mediating negative selection to ubiquitous antigens, we investigated the roles of both of these cell types in tolerance to TSAs. Here, we review our studies in which we found that mTECs were competent mediators of negative selection to a subset of TSA-reactive T cells, while thymic DCs extend the range of TSA-reactive T cells that undergo negative selection by capturing TSAs from mTECs. In addition, we recently investigated the efficiency of central tolerance to TSA during ontogeny, and we report that this process was less efficient in neonates than adult animals.

Age Factors↗

PubMed2004

Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation.

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.

Animals↗

PubMed2004

Driven to autoimmunity: the nod mouse.

In the lymphoid system, T cells respond to space or under-crowding by dividing to maintain their numbers. In this issue of Cell, evidence is provided that this homeostatic proliferation, coupled with excess production of a cytokine, IL-21, is a key factor in susceptibility to autoimmune diabetes.

Animals↗

PubMed2003

Surface expression of Notch1 on thymocytes: correlation with the double-negative to double-positive transition.

Notch1 plays a critical role in regulating T lineage commitment during the differentiation of lymphoid precursors. The physiological relevance of Notch1 signaling during subsequent stages of T cell differentiation has been more controversial. This is due in part to conflicting data from studies examining the overexpression or targeted deletion of Notch1 and to difficulties in distinguishing between the activities of multiple Notch family members and their ligands, which are expressed in the thymus. We employed a polyclonal antiserum against the extracellular domain of Notch1 to study surface expression during thymopoiesis. We found high levels of Notch1 on the cell surface only on double negative (DN) stage 2 through the immature single-positive stage of thymocyte development, before the double-positive (DP) stage. The Notch signaling pathway, as read out by Deltex1 expression levels, is highly active in DN thymocytes. When an active Notch1 transgene, Notch1IC, is exogenously introduced into thymocytes of recombinase-activating gene 2-deficient mice, it promotes proliferation and development to the DP stage following anti-CD3 treatment without apparently affecting the intensity of pre-TCR signaling. In addition, a stromal cell line expressing the Notch ligand, Delta-like-1, promotes the in vitro expansion of wild-type DN3 thymocytes in vitro. Consistent with other recent reports, these data suggest a role for Notch1 during the DN to DP stage of thymocyte maturation and suggest a cellular mechanism by which Notch1IC oncogenes could contribute to thymoma development and maintenance.

Animals↗