The goals of this application are to address the development of CD40+ T cells, the role that CD40 plays in T cell receptor (TCR) revision and how induced TCR revision impacts autoimmunity. CD40 has a direct role in autoimmune diseases including type 1 diabetes (T1D). We discovered that a unique subset of effector T cells, described as CD4loCD40+, are highly pathogenic in T1 D. CD40 is present on diabetogenic T cell clones and primary CD4loCD40+ T cells expand concurrently with insulitis in NOD mice. Importantly, CD4loCD40+ T cells readily transfer T1D to NOD.scid recipients. Mechanistically, CD40 induces the RAG1/RAG2 recombination machinery in T cells. Following that induction, TCR revision, induced alteration of TCR expression, occurs. Some revised primary T cells were found to be highly pathogenic. However, CD40 induced TCR revision could serve as a functional tolerance mechanism of established diabetogenic T cell clones. Specifically, CD40 engaging the diabetogenic T cell clone BDC2.5 severely ablated disease transfer ability of the clone. We showed that blocking CD40 - CD154 (the ligand for CD40) interaction in NOD mice at 3-weeks of age prevents not only T1D onset, but prevents expansion of CD4loCD40+, autoaggressive cells. In this application we will explore how CD40 affects the unique T cell population. Our hypothesis is that TCR revision directly impacts T cell tolerance.
Specific Aim #1 : Do CD4loCD40+ T cells comprise a unique T cell subset or represent a transient activation state within T cells? If CD40 is induced on T cells are there differences in those T cells compared to the intrinsic CD40 T cell subset? We plan experiments to address this central concern.
Specific Aim #2 : How does CD40 engagement affect TCR revision in CD4loCD40+ T cells? Are there differences in response to CD40 engagement between autoimmune and non-autoimmune conditions? We will explore RAG1 and RAG2 induction, kinetics of TCR revision and how different sources of CD154 in autoimmune versus non-autoimmune mice affect this process.
Specific Aim #3 : How does CD40 engagement affect T cell antigen specificity? We will explore how induced TCR revision affects T cell antigen specificity using in vitro and in vivo models. These proposed studies address not only the development of potential autoaggressive T cells but will provide important information as to whether induced TCR revision is pathogenic or tolerogenic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075013-05
Application #
8113290
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2007-08-01
Project End
2013-04-30
Budget Start
2011-08-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$272,906
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Vaitaitis, Gisela M; Olmstead, Michael H; Waid, Dan M et al. (2014) A CD40-targeted peptide controls and reverses type 1 diabetes in NOD mice. Diabetologia 57:2366-73
Vaitaitis, Gisela M; Wagner Jr, David H (2013) CD40 interacts directly with RAG1 and RAG2 in autoaggressive T cells and Fas prevents CD40-induced RAG expression. Cell Mol Immunol 10:483-9
Vaitaitis, Gisela M; Carter, Jessica R; Waid, Dan M et al. (2013) An alternative role for Foxp3 as an effector T cell regulator controlled through CD40. J Immunol 191:717-25
Vaitaitis, Gisela M; Wagner Jr, David H (2012) Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity. PLoS One 7:e38708
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Waid, Dan M; Vaitaitis, Gisela M; Pennock, Nathan D et al. (2008) Disruption of the homeostatic balance between autoaggressive (CD4+CD40+) and regulatory (CD4+CD25+FoxP3+) T cells promotes diabetes. J Leukoc Biol 84:431-9