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Eli Sercarz

Publications and source records attributed to Eli Sercarz.

8 recordsLinked to original sources
PubMed2006

T cells to a dominant epitope of GAD65 express a public CDR3 motif.

Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes, and serve as a model for type 1 diabetes (T1D) and natural autoimmunity. T cell responses to the pancreatic islet antigen glutamic acid decarboxylase 65 (GAD65) can be detected in the spleens of young prediabetic NOD mice, which display a unique MHC class II molecule. Here, we report that a distinct TcR beta chain and CDR3 motif are utilized by all NOD mice in response to a dominant determinant on GAD65, establishing a public repertoire in the spontaneous autoimmunity to an important islet cell antigen. GAD65 530-543 (p530)-reactive T cells preferentially utilize the Vbeta4, Dbeta2.1 and Jbeta2.7 gene segments, with a CDR3 that is characterized by a triad of amino acids, DWG, preceded by a polar residue. In addition, we used CDR3 length spectratyping, CDR3-specific reverse transcriptase-PCR and direct TcR sequencing to show that the TcR beta chain structural patterns associated with p530-specific T cells consistently appeared in the islets of young NOD mice with insulitis, but not in the inflamed islets of streptozotocin-treated C57BL/6 mice, or in inflamed NOD salivary glands. To our knowledge, this is the first report to demonstrate that a public T cell repertoire is used in spontaneous autoimmunity to a dominant self-determinant. These findings suggest that defined clonotypes and repertoires may be preferentially selected in haplotypes predisposed to spontaneous autoimmunity.

Amino Acid Motifs↗
PubMed2005

Clustering of T cell ligands on artificial APC membranes influences T cell activation and protein kinase C theta translocation to the T cell plasma membrane.

T cell activation is associated with active clustering of relevant molecules in membrane microdomains defined as the supramolecular activation cluster. The contact area between these regions on the surface of T cells and APC is defined as the immunological synapse. It has been recently shown that preclustering of MHC-peptide complexes in membrane microdomains on the APC surface affects the efficiency of immune synapse formation and the related T cell activation. Disruption of such clusters may reduce the efficiency of stimulation. We describe here an entirely artificial system for Ag-specific, ex vivo stimulation of human polyclonal T cells (artificial APC (aAPC)). aAPC are based on artificial membrane bilayers containing discrete membrane microdomains encompassing T cell ligands (i.e., appropriate MHC-peptide complexes in association with costimulatory molecules). We show here that preclustering of T cell ligands triggered a degree of T cell activation significantly higher than the one achieved when we used either soluble tetramers or aAPC in which MHC-peptide complexes were uniformly distributed within artificial bilayer membranes. This increased efficiency in stimulation was mirrored by increased translocation from the cytoplasm to the membrane of protein kinase theta, a T cell signaling molecule that colocalizes with the TCR within the supramolecular activation cluster, thus indicating efficient engagement of T cell activation pathways. Engineered aAPC may have immediate application for basic and clinical immunology studies pertaining to modulation of T cells ex vivo.

Antigen-Presenting Cells↗
PubMed2005

Antigen processing by autoreactive B cells promotes determinant spreading.

Acute primary immune responses tend to focus on few immunodominant determinants using a very limited number of T cell clones for expansion, whereas chronic inflammatory responses generally recruit a large number of different T cell clones to attack a broader range of determinants of the invading pathogens or the inflamed tissues. In T cell-mediated organ-specific autoimmune disease, a transition from the acute to the chronic phase contributes to pathogenesis, and the broadening process is called determinant spreading. The cellular components catalyzing the spreading reaction are not identified. It has been suggested that autoreactive B cells may play a central role in diversifying autoreactive T cell responses, possibly through affecting antigen processing and presentation. The clonal identity and diversity of the B cells and antibodies seem critical in regulating T cell activity and subsequent tissue damage or repair. Here, we use two autoimmune animal models, experimental autoimmune thyroiditis (EAT) and type 1 diabetes (T1D), to discuss how autoreactive B cells or antibodies alter the processing and presentation of autoantigens to regulate specific T cell response.

Animals↗
PubMed2003

The adaptor protein AP-3 is required for CD1d-mediated antigen presentation of glycosphingolipids and development of Valpha14i NKT cells.

Relatively little is known about the pathway leading to the presentation of glycolipids by CD1 molecules. Here we show that the adaptor protein complex 3 (AP-3) is required for the efficient presentation of glycolipid antigens that require internalization and processing. AP-3 interacts with mouse CD1d, and cells from mice deficient for AP-3 have increased cell surface levels of CD1d and decreased expression in late endosomes. Spleen cells from AP-3-deficient mice have a reduced ability to present glycolipids to natural killer T (NKT) cells. Furthermore, AP-3-deficient mice have a significantly reduced NKT cell population, although this is not caused by self-tolerance that might result from increased CD1d surface levels. These data suggest that the generation of the endogenous ligand that selects NKT cells may also be AP-3 dependent. However, the function of MHC class II-reactive CD4+ T lymphocytes is not altered by AP-3 deficiency. Consistent with this divergence from the class II pathway, NKT cell development and antigen presentation by CD1d are not reduced by invariant chain deficiency. These data demonstrate that the AP-3 requirement is a particular attribute of the CD1d pathway in mice and that, although MHC class II molecules and CD1d are both found in late endosomes or lysosomes, different pathways mediate their intracellular trafficking.

Adaptor Protein Complex 3↗
PubMed2003

Regulatory T cells control autoimmunity in vivo by inducing apoptotic depletion of activated pathogenic lymphocytes.

Clinical autoimmunity requires both activation of self-reactive T cells as well as a failure of peripheral tolerance mechanisms. We previously identified one such mechanism that involves regulatory T cells recognizing TCR V beta 8.2 chain-derived peptides in the context of MHC. How this regulation affects the fate of target V beta 8.2(+) T lymphocytes in vivo that mediate experimental autoimmune encephalomyelitis has remained unknown. The present study using immunoscope and CFSE-labeling analysis demonstrates that the expansion of regulatory CD4 and CD8 T cells in vivo results in apoptotic depletion of the dominant, myelin basic protein-reactive V beta 8.2(+) T cells, but not subdominant V beta 13(+) T cells. The elimination of only activated T cells by this negative feedback mechanism preserves the remainder of the naive V beta 8.2(+) T cell repertoire and at the same time results in protection from disease. These studies are the first in clearly elucidating the fate of myelin basic protein-specific encephalitogenic T cells in vivo following regulation.

Amino Acid Sequence↗
PubMed2003

Seven surprises in the TCR-centred regulation of immune responsiveness in an autoimmune system.

Self-reactivity is potentially so devastating to the organism that a variety of regulatory devices have evolved to control it. One broadly used strategy is that employing the processed T cell receptor (TCR) as a target for TCR-specific regulatory cells. In several autoimmune models, feedback regulation employing both CD4+ and CD8+ T cells of TCR specificity can be shown to occur and to account for remission from the transient disease state, or for its prevention. We will focus here on the experimental autoimmune encephalomyelitis (EAE) model in the B10.PL (H-2u) mouse. In this model, the acetylated 1-9 N-terminal antigenic determinant from myelin basic protein (MBP) induces a transient paralytic disease owing to the activation of self-directed, high-affinity, CD4+ T cells. Although the response is multiclonal, a particularly aggressive member of this repertoire, bearing a Vbeta8.2,Jbeta2.7 receptor, which we have termed a 'driver clone', appears to be largely responsible for the disease process. A CD4+ T cell directed against a TCR determinant in the framework region of the Vbeta chain, and a CD8+ T cell directed against an upstream, distinct framework determinant, both of which are necessary for regulation, bring about a reversal of the disease process. To accomplish this, there must be a Th1 milieu during the induction of regulation, which is provided in part by the CD4+ regulatory cells themselves. To act as a target, the Vbeta8.2 MBP-reactive T cell must be activated, and the Th1 driver clone(s) is down-regulated via apoptotic killing, leaving a group of Th2, MBP-specific clones of weak affinity, which themselves may help in perpetuating long-term regulation. Similar results are also found in the collagen arthritis and NOD diabetes models.

Animals↗
PubMedDate not supplied

Feedback regulation of autoimmunity via TCR-centered regulation.

The complexity of a self-regulatory system demands a balance between effectors and regulators; that is, it is necessary for both cell types to exist. Regulation of self-reactive T cells can occur at several complementary but different levels: (1) at the level of priming itself: for example, inhibition of expansion of antigen-reactive T cells by regulatory CD4+ CD25+ T cells; (2) after the priming of self-reactive T cells, regulatory T-cell populations with reactivity to distinct self-determinants derived from the T-cell receptor (TCR) can be engaged via a negative feedback mechanism. Thus, these mechanisms ensure induction of effective and appropriately limited responses against foreign antigens while preventing autoreactivity from inflicting self-damage.

Animals↗