A major activity of iNKT cells is to control dendritic cell (DC) migration, maturation and effector function. Hence, the interactions of iNKT cells with DC are critical bridges between innate and acquired immunity. DC provide this linkage, in part, through pattern recognition receptors (e.g., toll like receptors (TLR), retinoic acid- induce gene 1-like-receptors (RLR) and NOD-like receptors (NLR) that "detect" bacterial/viral/biochemical and "self" molecular signatures leading to immune activation. DC activated by TLR produce inflammatory cytokines, most notably for the licensing of iNKT cell activation, Type 1 interferons (IFNa/b) and IL-12p70. Hence, iNKT cells provide a critical element at the interface of innate and adaptive immune responses and through this activity, may play a key role in the pathogenesis of type 1 diabetes (T1D). This notion fits well within the overall hypothesis of this RO1 that individuals with or at increased-risk for T1D have multiple disease susceptibility genes imparting systemic immunoregulatory abnormalities such as those resulting in defects in iNKT cell and DC function. Indeed, in rodent models of spontaneous autoimmune diabetes, CD4+ iNKT regulatory as opposed to pro-inflammatory DN iNKT cells are selectively lost in the pancreas and PLN. Despite strong evidence that exists in the NOD mice for this notion the iNKT data in human T1D is controversial, with little or no understanding of the question as to what is occurs in these tissues in T1D patients. Recent work suggests that CD4+ iNKT cells strongly induce the maturation of tolerogenic myeloid DC. How this is process is effected in T1D remains a critical question. Selective deficiencies in CD4+ iNKT cells results in defective generation of tolerogenic DC and accelerated disease in NOD mice. Transfer of CD4+ iNKT cells or iNKT-conditioned DC protects NOD mice from disease. Importantly, and in stark contrast to the traditional role of TLR activation, we have purified and validated an endogenous TLR4 ligand, S100A8, selectively secreted by CD4+ iNKT cells that induces tolerogenic DC. These tolerogenic DC potently induce differentiation of CD4+ Foxp3+ Treg from na?ve precursors. Based on these results the following aims will test the hypothesis that genetically regulated defects in Plasmacytoid DC (PDC) / IFNa/b production inhibits the ability CD4+ iNKT cells to induce tolerogenic myeloid DC differentiation via novel TLR4-dependent pathways contributing to the development of pathogenic autoimmune T cells and T1D.

Public Health Relevance

A major activity of iNKT cells is to control dendritic cell (DC) migration, maturation and effector function. Hence, the interactions of iNKT cells with DC are critical bridges between innate and acquired immunity. DC provide this linkage, in part, through pattern recognition receptors (e.g., toll like receptors (TLR), that detect bacterial/viral/biochemical and self molecular signatures leading to immune activation. Indeed, in rodent models of spontaneous autoimmune diabetes, CD4+ iNKT regulatory as opposed to pro-inflammatory DN iNKT cells are selectively lost in the pancreas and its draining lymph nodes. Recent work suggests that CD4+ iNKT cells strongly induce the maturation of tolerogenic myeloid DC. How this is process is effected in T1D remains a critical question. Importantly, and in stark contrast to the traditional role of TLR activation, we have purified and validated an endogenous TLR4 ligand, S100A8, selectively secreted by CD4+ iNKT cells that induces tolerogenic DC. Based on these results we will test whether genetically regulated defects in DC and iNKT via IFNa/b production inhibits the ability CD4+ iNKT cells to induce tolerogenic myeloid DC differentiation via novel TLR4-dependent pathways contributing to the development of pathogenic autoimmune T cells and T1D.

Agency
National Institute of Health (NIH)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI113057-01
Application #
8880308
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bourcier, Katarzyna
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Gainesville
State
FL
Country
United States
Zip Code
32611