Immunological tolerance through mucosal antigen exposure is allergen-specific, highly effective and long lasting. Although such features should make it suitable for the treatment of immunological diseases, current protocols of specific immunotherapy rarely take advantage of it. Better knowledge of the mechanisms might simplify treatments and help avoid potentially dangerous exposures. It is known that mucosal tolerance to inhaled antigens can be mediated by 34 T cells. In cell transfer experiments in mice, splenic 34 T cells from donors tolerized by repeated antigen inhalation were shown to suppress the IgE response to the antigen with surprisingly high efficiency, while leaving IgG levels unchanged. Although 34 T cells are not normally selected by conventional antigens, the IgE suppression appeared to be antigen-specific, but the underlying mechanism was not determined. We have characterized the IgE suppressive 34 T cells in the spleen, and our preliminary data now provide direct support for their antigen-specificity. Moreover, our new data suggest that these 34 T cells are induced by splenic dendritic cells (DCs), and function themselves as antigen presenting cells (APCs), preventing the development of T helper 2 (Th2) cells. We hypothesize that the ability of 34 T cells to regulate T-dependent specific IgE antibodies is directly linked to their inducible antigen presenting function. Specifically, we now envisage a pathway in which inhaled antigen, initially absorbed in the lung, is released into the circulation, retrieved in the spleen and, along with activating signals, passed on by splenic dendritic cells (DCs) to splenic 34 T cells, which differentiate into APCs. Dictated by their own functional bias, the 34 T cell-APCs then modulate T-dependent Ig switch recombination in B cells. The 34 T cells of the IgE suppressor-type in this study (V34+CD82+IFN-3+) reduce specific IgE antibody. We propose to test this hypothesis and investigate the processes involved by determining whether antigen is transferred to the IgE regulatory 34 T cells, and if these cells can function as APCs for the inhaled antigen. We will also determine whether inhalation-induced IgE suppressive 34 T cells regulate antigen-specific Th2 differentiation, and if IFN-3 is a crucial mediator in their regulatory control. Finally, we will examine if the IgE-regulatory function of the 34 T cells, which requires induction by MyD88+ DCs, relies on Th1-inducing cytokines produced by these DCs, such as IL-12. These studies should provide a better understanding of natural, 34 T cell-mediated, control mechanisms in allergic responses, and their potential uses for therapeutic intervention.
Human protection against parasitic pathogens partially relies on antibodies known as IgE. Unfortunately, IgE antibodies also mediate harmful allergic reactions to inert environmental substances known as allergens. However, repeated inhalation of allergens can induce a state of tolerance and prevent later allergic reactions. The underlying mechanism is not yet well understood. In this application, we propose to investigate the action of a distinct cell type, known as 34 T cell, which, following allergen inhalation, can prevent development of IgE antibodies. Our planned experiments should reveal how the regulatory function of these 34 T cells is induced, and determine how they exert their regulatory control. This new information about 34 T cell functions in IgE regulation will be helpful in developing better approaches to the control of IgE in allergic diseases.
|Zeng, Wanjiang; O'Brien, Rebecca L; Born, Willi K et al. (2018) Characterization of Mouse ?? T Cell Subsets in the Setting of Type-2 Immunity. Methods Mol Biol 1799:135-151|
|Huang, Yafei; Getahun, Andrew; Heiser, Ryan A et al. (2016) ?? T Cells Shape Preimmune Peripheral B Cell Populations. J Immunol 196:217-31|
|Huang, Yafei; Heiser, Ryan A; Detanico, Thiago O et al. (2015) ?? T cells affect IL-4 production and B-cell tolerance. Proc Natl Acad Sci U S A 112:E39-48|
|Huang, Yafei; Aydintug, M Kemal; Loomis, Joshua et al. (2013) Antigen-specific regulation of IgE antibodies by non-antigen-specific ?? T cells. J Immunol 190:913-21|