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Biomedical subjects

Ana C Anderson

Publications and source records attributed to Ana C Anderson.

7 recordsLinked to original sources
PubMed2006

TIM-3 in autoimmunity.

T cell immunoglobulin and mucin domain (TIM)-3 is a molecule expressed on terminally differentiated murine Th1 cells but not on Th2 cells. Identification of galectin-9 as a ligand for TIM-3 has now firmly established the TIM-3-galectin-9 pathway as an important regulator of Th1 immunity and tolerance induction. TIM-3 is similarly expressed on human Th1 cells and not on Th2 cells, which suggests that TIM-3 might also contribute to Th1 regulation in humans. In addition, genetic data associate the TIM locus and specific TIM-3 polymorphisms with various immune-mediated diseases. Most importantly, recent data suggest a novel paradigm in which dysregulation of the TIM-3-galectin-9 pathway could underlie chronic autoimmune disease states, such as multiple sclerosis.

Animals↗
PubMed2005

The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.

Tim-3 is a T helper type 1 (T(H)1)-specific cell surface molecule that seems to regulate T(H)1 responses and the induction of peripheral tolerance. However, the identity of the Tim-3 ligand and the mechanism by which this ligand inhibits the function of effector T(H)1 cells remain unknown. Here we show that galectin-9 is the Tim-3 ligand. Galectin-9-induced intracellular calcium flux, aggregation and death of T(H)1 cells were Tim-3-dependent in vitro, and administration of galectin-9 in vivo resulted in selective loss of interferon-gamma-producing cells and suppression of T(H)1 autoimmunity. These data suggest that the Tim-3-galectin-9 pathway may have evolved to ensure effective termination of effector T(H)1 cells.

Amino Acid Sequence↗
PubMed2005

Impairment of thymocyte development by dominant-negative Kuzbanian (ADAM-10) is rescued by the Notch ligand, delta-1.

Although Notch plays a crucial role in T cell development, regulation of Notch signaling in the thymus is not well understood. Kuzbanian, an ADAM protease, has been implicated in the cleavage of both Notch receptors and the Notch ligand, Delta. In this study we show that the expression of a dominant-negative form of Kuzbanian (dnKuz) leads to reduced TCRbeta expression in double-negative thymocytes and to a partial block between the double-negative to double-positive stages of development. These defects were rescued by overexpression of Delta-1 on thymocytes. Mixed chimeras showed a cell-autonomous block by dnKuz, but non-cell-autonomous rescue by Delta-1. This suggests that dnKuz impairs Notch signaling in receiving cells, and increasing Delta-1 on sending cells overcomes this defect. Interestingly, the expression of an activated form of Notch-1 rescued some, but not all, the defects in dnKuz Tg mice. Our data suggest that multiple Notch-dependent steps in early thymocyte development require Kuzbanian, but differ in the involvement of other Notch signaling components.

ADAM Proteins↗
PubMed2005

The Notch regulator Numb links the Notch and TCR signaling pathways.

Both the Notch and TCR signaling pathways play an important role in T cell development, but the links between these signaling pathways are largely unexplored. The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways. We explored this possibility by investigating the physical interactions among Notch, Numb, and the TCR signaling apparatus and by examining the consequences of a Numb mutation on T cell development. We found that Notch and Numb cocluster with the TCR at the APC contact during Ag-driven T cell-APC interactions in both immature and mature T cells. Furthermore, Numb coimmunoprecipitates with components of the TCR signaling apparatus. Despite this association, T cell development and T cell activation occur normally in the absence of Numb, perhaps due to the expression of the related protein, Numblike. Together our data suggest that Notch and TCR signals may be integrated at the cell membrane, and that Numb may be an important adapter in this process.

Animals↗
PubMed2004

IL-10 plays an important role in the homeostatic regulation of the autoreactive repertoire in naive mice.

We have previously shown that naive SJL (H-2(s)) mice, which are highly susceptible to myelin proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), have a very high frequency (1/20,000 CD4 T cells) of PLP(139-151)-reactive T cells in the naive repertoire. In this study, we examine the function of this endogenous PLP(139-151)-reactive repertoire in vivo and find that this repertoire encompasses the precursors of pathogenic T cells. Because SJL mice do not develop spontaneous EAE, we have explored the mechanisms that keep this autopathogenic repertoire in check and prevent the development of spontaneous autoimmunity. We crossed IL-4 and IL-10 deficiency onto the SJL background and analyzed the roles of these two immunoregulatory cytokines in regulating the size and effector function of the endogenous PLP(139-151)-reactive repertoire and development of autoimmune disease. We find that IL-10 is important in the homeostatic regulation of the endogenous PLP(139-151)-reactive repertoire in that it both limits the size of the repertoire and prevents development of effector autoaggressive T cells. SJL IL-10(-/-) mice with high numbers of PLP(139-151)-specific precursors in the repertoire did not develop spontaneous EAE, but when they were injected with pertussis toxin, they showed atypical clinical signs of EAE with small numbers of typical mononuclear cell infiltrates predominantly in the meninges. EAE could be inhibited by prior tolerization of the mice with soluble PLP(139-151) peptide. These findings indicate that IL-10 may contribute to the regulation of the endogenous autoimmune repertoire.

Adoptive Transfer↗
PubMed2001

T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire.

T cells that can respond to self-antigens are present in the peripheral immune repertoire of all healthy individuals. Recently we have found that unmanipulated SJL mice that are highly susceptible to EAE also maintain a very high frequency of T cells responding to an encephalitogenic epitope of a myelin antigen proteolipid protein (PLP) 139-151 in the peripheral repertoire. This is not due to lack of expression of myelin antigens in the thymus resulting in escape of PLP 139-151 reactive cells from central tolerance, but is due to expression of a splice variant of PLP named DM20, which lacks the residues 116-150. In spite of this high frequency, the PLP 139-151 reactive cells remain undifferentiated in the periphery and do not induce spontaneous EAE. In contrast, SJL TCR transgenic mice expressing a receptor derived from a pathogenic T cell clone do develop spontaneous disease. This may be because in normal mice, autoreactive cells are kept in check by an alternate PLP 139-151 reactive nonpathogenic repertoire, which maintains a balance that keeps them healthy. If this is the case, selective activation of one repertoire or the other may alter susceptibility to autoimmune disease. Since T cells are generally cross-reactive, besides responding to nonself-antigens, they also maintain significant responses to self-antigens. Based on the PLP 139-151 system, we propose a model in which activation with foreign antigens can result in the generation of pathogenic memory T cells that mediate autoimmunity. We also outline circumstances under which activation of self-reactive T cells with foreign antigens can generate selective tolerance and thus generate protective/regulatory memory against self while still maintaining significant responses against foreign antigens. This provides a mechanism by which the fidelity and specificity of the immune system against foreign antigens is improved without increasing the potential for developing an autoimmune disease.

Amino Acid Sequence↗