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.
|Waid, Dan M; Schreiner, Teri; Vaitaitis, Gisela et al. (2014) Defining a new biomarker for the autoimmune component of Multiple Sclerosis: Th40 cells. J Neuroimmunol 270:75-85|
|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|
|Jun, Du; Garat, Chrystelle; West, James et al. (2011) The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation. Stem Cells 29:725-35|
|Chow, Kelsey S; Jun, DuHyun; Helm, Karen M et al. (2011) Isolation & characterization of Hoechst(low) CD45(negative) mouse lung mesenchymal stem cells. J Vis Exp :e3159|
|Vaitaitis, Gisela M; Wagner Jr, David H (2010) CD40 glycoforms and TNF-receptors 1 and 2 in the formation of CD40 receptor(s) in autoimmunity. Mol Immunol 47:2303-13|
|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|