Variations in Antigen Presentation Define Regulatory T Cell formation and Activity in Vivo

The studies presented in this dissertation examine how the formation, differentiation, and activity of Foxp3+ regulatory T (Treg) cells can be affected by variations in the amount of a cognate antigen (Ag) that is present, the cell types by which it is expressed and/or presented, and whether Ag recognition occurs in an inflammatory environment. Recognition of a weakly immunostimulatory self-peptide was able to promote both thymic CD4+Foxp3+ Treg cell development and the formation of CD4+Foxp3+ Treg cells from CD4+Foxp3- T cell precursors in the periphery. Despite promoting Treg cell formation, this weakly immunostimulatory self-Ag was unable to induce Treg cell activity during influenza virus infection. Conversely, when the same Ag was derived from an influenza virus, it drove Treg cells to proliferate and acquire a T-bet+CXCR3+ phenotype, and to suppress the accumulation of CD4+Foxp3- and CD8+ effector T cells in the lungs of infected mice. Notably, when cognate Ag was expressed at high levels by antigen presenting cells, Treg cells also underwent substantial proliferation, but little or no differentiation into a T-bet+CXCR3+ phenotype occurred, and their ability to modulate an anti-viral immune response was impaired. This failure to promote the formation of T-bet+CXCR3+Foxp3+ Treg cells could be attributed in part to the presentation of the cognate Ag by B cells, and in part to their initial activation by a highly stimulatory Ag in a non-inflammatory environment. Interactions with cognate peptide:MHC complex in these contexts diminished the ability of Treg cells to differentiate upon subsequent exposure to cognate Ag when it was derived from virus and presented by dendritic cells in the lung-draining mediastinal lymph nodes. Collectively, these studies show that the mode of presentation of an Ag can critically affect the formation and activity of Foxp3+ Treg cells in vivo, and that the type of antigen presenting cell and inflammatory environment encountered during their initial activation can determine their ability to differentiate into novel effector phenotypes