Project Summary: Type-1 diabetes (T1D) is caused by autoreactive T cells that selectively destroy insulin-secreting b cells in the pancreas. Loss of immunological tolerance to b cells causes T1D, but the underlying mechanisms are poorly understood, preventing the development of a cure for T1D. A major component of peripheral tolerance to prevent T1D is the regulation of circulating autoreactive T cells in lymph nodes (LNs) by interactions with tolerogenic Ag- presenting cells (APCs) and regulatory T cells, both of which appear to be defective in T1D. Fibroblastic reticular cells (FRCs) form the LN reticula that guide migration and interactions of T cells and APCs. FRCs are also responsible for remodeling the LN and allowing its expansion during inflammation. Relevant to autoimmune diseases, FRCs are non-professional APCs that can induce antigen-specific tolerance by expressing and presenting antigens to specific T cells without co-stimulatory signals, leading to T cell engagement (stimulation and proliferation) followed by deletion. Most studies have been done using transgenic mice for overexpression of artificial (not disease relevant) antigens in FRCs; thus, the role of FRCs in maintaining peripheral tolerance to disease-relevant self-antigens is poorly understood. We found that in T1D, relative frequency, antigen expression levels and reticular organization of LN FRCs are affected. One goal of this proposal is to use innovative tissue-engineered FRC reticula that recapitulate FRC reticular organization in the LN paracortex and T1D known self-antigen expression to study how FRC reticular properties (aim 1.1) and antigens expression levels (aim 2.1) affect T cell engagement in vitro through co-culture studies. While professional APCs can switch to immunogenic phenotypes and promote T1D, non-professional APCs like FRCs are less likely to do so. We showed that promoting formation of FRC reticula expressing T1D antigens is sufficient to induce tolerance and prevent T1D in non-obese diabetic (NOD) mice. Thus, a second goal of this proposal is to test in NOD mice whether we can delete autoreactive T cells from the systemic circulation to ameliorate T1D by (i) attracting them to implanted engineered reticula and by (ii) promoting tolerogenic T cell engagement by modulating FRC reticular properties (aim 1.2) and/or FRC antigen-expression levels (aim 2.2).
|Effective start/end date||12/1/20 → 11/30/21|
- National Institute of Allergy and Infectious Diseases: $432,804.00
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