Curative therapy for autoimmune diseases will require reinstitution of immunological tolerance within those T and B cells that have lost the capacity to peacefully co-exist with self antigen. However, a lack of knowledge regarding the induction and maintenance of antigen-specific unresponsiveness (clonal anergy) hampers the development of such tolerance-inducing regimens. In the previous grant period, we reported that co- expression of Folate receptor-4 (FR4) and CD73 is strongly associated with the development of clonal anergy in pathogenic CD4+ T cells. Furthermore, we showed that the development and maintenance of anergy in these autoreactive CD4+ T cells was highly dependent on the activity of polyclonal Foxp3+ Tregs. We have now observed that the induction and maintenance of anergy is associated with the up-regulation of the lineage-directing nuclear factor C/EBP alpha during self antigen recognition. Furthermore, we have found that antigen-experienced polyclonal CD4+ T cells having a FR4hi CD73hi phenotype differentiate to Th1 and Tfh lineages that cause disease when transferred into lymphopenic hosts under conditions that prevent Foxp3+ Treg generation. Accordingly, the goals ofthe current proposal are to 1) determine the unique roles that Foxp3+ Tregs, yc cytokine receptors, TSC1, mTOR, and C/EBP alpha play in autoreactive CD4+ T cell clonal anergy reversal and differentiation to T effector/memory cell versus Foxp3+ T regulatory cell phenotypes, and 2) investigate the pathogenicity of a novel 'Anergic'CD44hi FR4hi CD73hi Foxp3- polyclonal CD4+ T cell subset, and determine the roles that C/EBPalpha and the Foxp3 CNS1 DNA sequence play in the differentiation of anergic self Ag-specific progenitor cells to either dangerous T effector/memory cell or protective Foxp3+ ITreg phenotypes. Ultimately, we intend to understand the effects of altered peripheral T cell homeostasis and deficient or dysfunctional Tregs on the reversal of anergy, to tip the balance back away from the differentiation of dangerous T effector/memory cells to the generation of ITregs capable of inducing and maintaining antigen-specific self tolerance.

Public Health Relevance

Autoimmune diseases such as RA and SLE are caused by self antigen-specific T cells normally kept in check (an anergic state) by T regulatory cells. We can now identify these autoreactive T cells in normal individuals, and make them into either dangerous T effector or protective T regulatory cells. Experiments will explore the molecular mechanisms involved in this induction and maintenance of anergy.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AI035296-21
Application #
8662147
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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