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Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells
Hélène Bour-Jordan, … , Matthew R. Bernhard, Jeffrey A. Bluestone
Hélène Bour-Jordan, … , Matthew R. Bernhard, Jeffrey A. Bluestone
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):979-987. https://doi.org/10.1172/JCI20483.
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Article Autoimmunity

Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells

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Abstract

The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse results from a breakdown in tolerance to pancreatic islet antigens. CD28-B7 and CD40 ligand–CD40 (CD40L-CD40) costimulatory pathways affect the development of disease and are promising therapeutic targets. Indeed, it was shown previously that diabetes fails to develop in NOD–B7-2–/– and NOD-CD40L–/– mice. In this study, we examined the relative role of these 2 costimulatory pathways in the balance of autoimmunity versus regulation in NOD mice. We demonstrate that initiation but not effector function of autoreactive T cells was defective in NOD–B7-2–/– mice. Moreover, the residual proliferation of the autoreactive cells was effectively controlled by CD28-dependent CD4+CD25+ regulatory T cells (Treg’s), as depletion of Treg’s partially restored proliferation of autoreactive T cells and resulted in diabetes in an adoptive-transfer model. Similarly, disruption of the CD28-B7 pathway and subsequent Treg deletion restored autoimmunity in NOD-CD40L–/– mice. These results demonstrate that development of diabetes is dependent on a balance of pathogenic and regulatory T cells that is controlled by costimulatory signals. Thus, elimination of Treg’s results in diabetes even in the absence of costimulation, which suggests a need for alternative strategies for immunotherapeutic approaches.

Authors

Hélène Bour-Jordan, Benoît L. Salomon, Heather L. Thompson, Gregory L. Szot, Matthew R. Bernhard, Jeffrey A. Bluestone

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Figure 5

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CD28 and CD40L differentially affect diabetes in NOD mice. (A) We develo...
CD28 and CD40L differentially affect diabetes in NOD mice. (A) We developed NOD mice deficient for CD28 (NOD-CD28_/_), CD40L (NOD-CD40L_/_), or both CD40L and CD28 (NOD-CD40L_/_CD28_/_). We compared the number of Treg’s in these different strains. The results are displayed as CD62L (y axis) versus CD25 (x axis) staining and are gated on the CD4+ population. One out of 3 representative experiments is shown. (B) We compared the incidence of diabetes in NOD (open squares), NOD-CD28_/_ (open triangles), NOD-CD40L_/_ (x’s) and NOD-CD40L_/_CD28_/_ (filled squares) mice. (C) We performed histological analysis of the pancreas in NOD-CD40L_/_ and NOD-CD40L_/_CD28_/_ mice and scored the severity of insulitis as peri-insulitis (white bars), moderate insulitis (gray bars) and severe insulitis (black bars) in NOD-CD40L_/_ and NOD-CD40L_/_CD28_/_ mice (70 and 37 islets were scored, respectively). (D) CD25-depleted BDC2.5-CD90.1 T cells were labeled with CFSE and transferred into NOD or NOD-CD28_/_ mice. Four days later, the proliferation of BDC2.5 cells was assessed in the pancreatic LNs. The histograms are gated on CD4+ CD90.1+ cells, and the 3 regions M1_M3 indicate undivided cells, cells that underwent 1 to 3 divisions, and cells that underwent 4 or more divisions, respectively.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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