Regulatory T Cell Control of Autoimmune Destruction of Beta Cells In The BB Rat

Greiner, Dale L.; Angelillo, M; Mordes, John P.; Handler, Eugene S.; Mojcik, Christopher F.; Nakamura, Naoto; Rossini, Aldo A.

doi:10.1007/978-1-4684-5616-5_46

Cited by 25 publications

(31 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our model may be the observation that depleting rats or mice of T cells expressing ART-2 accelerates development of autoimmune diabetes and lupus erythematosus (34,35). This could be explained by a mechanism in which NAD released from cells controls effector T cells.…”

Section: Discussionsupporting

confidence: 84%

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

Kawamura

Aswad

Minagawa

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Adding NAD to murine T lymphocytes inhibits their functions and induces annexin V binding. This report shows that NAD induces cell death in a subset of T cells within seconds whereas others do not die until many hours later. Low NAD concentrations (<10 μM) suffice to trigger rapid cell death, which is associated with annexin V binding and membrane pore formation, is not blocked by the caspase inhibitor Z-VADfmk, and requires functional P2X7 receptors. The slower induction of death requires higher NAD concentrations (>100 μM), is blocked by caspase inhibitor Z-VADfmk, is associated with DNA fragmentation, and does not require P2X7 receptors. T cells degrade NAD to ADP-ribose (ADPR), and adding ADPR to T cells leads to slow but not rapid cell death. NAD but not ADPR provides the substrate for ADP-ribosyltransferase (ART-2)-mediated attachment of ADP-ribosyl groups to cell surface proteins; expression of ART-2 is required for NAD to trigger rapid but not slow cell death. These results support the hypothesis that cell surface ART-2 uses NAD but not ADPR to attach ADP-ribosyl groups to the cell surface, and that these groups act as ligands for P2X7 receptors that then induce rapid cell death. Adding either NAD or ADPR also triggers a different set of mechanisms, not requiring ART-2 or P2X7 receptors that more slowly induce cell death.

show abstract

Section: Discussionsupporting

confidence: 84%

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

Kawamura

Aswad

Minagawa

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Breakdown of tolerance to islet cell Ags during the natural development of diabetes has been ascribed to the genetic lack of RT6 ϩ Treg cells in DP-BB rats (17) and to the age-dependent decline of Treg cell function in NOD mice (18,19). Failure of Treg cells was also assigned for the exacerbated autoimmunity observed in lymphopenic d3-Tx mice (4).…”

mentioning

confidence: 99%

Autoimmunity during Thymectomy-Induced Lymphopenia: Role of Thymus Ablation and Initial Effector T Cell Activation Timing in Nonobese Diabetic Mice

Gagnerault

Lanvin²,

Pasquier³

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

Autoimmune diseases develop in selected normal mouse strains when thymectomy (Tx) is performed at 3 days of age (d3-Tx). Insufficient T cell regulation after Tx may result from a defect in regulatory T (Treg) cells or from an augmented effector T (Teff) cell number/pathogenicity. We have previously shown that Tx at 3 wk (wk3-Tx), the age of massive islet Ag release, accelerates diabetes onset. We now have determined diabetes incidence in d3-Tx nonobese diabetic mice and compared the frequency and function of their Teff and Treg cells with those of wk3-Tx mice. We found that d3-Tx had no effect on diabetes incidence, but induced gastritis. After day 3 and week 3 Tx, Treg cells were fully competent and their frequency increased. The number of diabetogenic T cells was greatly amplified after wk3-Tx and likely overcame Treg cell control, leading to an early tolerance breakdown. By contrast, in d3-Tx mice, activation concerned few cells and Teff cell amplification remained controlled. This suggests that Tx enhances autoimmunity when it coincides with the first encounter of autoreactive T cells with their cognate Ag. The relationship between Tx-induced lymphopenia, tissue remodeling, and autoimmunity is discussed.

show abstract

“…BBDR rats never become diabetic if housed in a clean environment. If, however, we use a monoclonal antibody (mAb) to deplete the ART2 ϩ regulatory T-cells in these animals, we disequilibrate the system and induce diabetes (28). An even more interesting discovery was that a naturally occurring infection, specifically with Kilham rat virus (KRV) can also disequilibrate the system (29).…”

Section: The Circle Of Tolerance: Pathogenesis and Preventionmentioning

confidence: 99%

Autoimmune Diabetes and the Circle of Tolerance

Rossini

2004

Diabetes

Self Cite

View full text Add to dashboard Cite

The concept of immunological tolerance is central to our understanding of type 1 diabetes and the development of strategies for its prediction, prevention, and cure. Tolerance simply refers to the absence of an immune response. Most of us are born with an immune system that develops tolerance to all the other systems of our bodies as well as to the things that we eat. It is the loss of immunological tolerance that leads to autoimmunity. And when that autoimmune response directly or indirectly targets the ␤-cell, type 1 diabetes is the result. In the U.S., 1 in 600 of us loses tolerance to pancreatic ␤-cells. Interference with T-cell function after the loss of tolerance, as can be achieved with immunosuppressive drugs like cyclosporin, arrests the disease, but the cost in side effects is high. Clearly, stopping the loss of tolerance would be preferable. If we can stop the loss of tolerance, we can prevent the disease. We and many others have investigated both approaches. But what of the people who already have diabetes? For them a separate but related strategy, tolerance induction, is required. Specifically, islet transplantation tolerance induction holds out the promise of being able to cure the disease. This has been the ultimate goal of our laboratory's work for the past two decades. Diabetes 53: [267][268][269][270][271][272][273][274][275] 2004

show abstract

Regulatory T Cell Control of Autoimmune Destruction of Beta Cells In The BB Rat

Cited by 25 publications

References 7 publications

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

Autoimmunity during Thymectomy-Induced Lymphopenia: Role of Thymus Ablation and Initial Effector T Cell Activation Timing in Nonobese Diabetic Mice

Autoimmune Diabetes and the Circle of Tolerance

Contact Info

Product

Resources

About