Interleukin 4 (IL-4), which is produced by lymphocytes and myeloid cells, is an early multifunctional cytokine with profound effects on the immune system and the immune responses. Many of its effects are mediated through IgE antibodies. IL-4 affords host protection against infections with parasites, and it can prevent damaging autoimmunity, but it also potentially hinders protective immune responses against bacterial and viral infections, exacerbates allergic immune responses and enables anaphylactic reactivity. The production of IL-4 is regulated at multiple levels. Much is already known about the molecular control of IL-4 gene expression, as well as cellular interactions regulating IL-4 production in the course of an immune response. Here, IL-4 itself plays an important role in positive feedback control. In contrast, far less is known about regulatory mechanisms in the early development of cells capable of producing IL-4, especially innate cell types, which mature independently of IL-4 signals. The proposed project aims at elucidating this initial regulation, which, prior to any immune response, lays the tracks for later immune competence of the whole organism. We just reported that mice genetically deficient in certain ?? T cells (B6.V?4/6KO) exhibit pathologically increased IL-4-production, and a loss of B cell tolerance. The phenotype includes high levels of IgE before and after immunization, as well as further changes similar to those seen associated with pathologically high IgE antibodies in humans. In contrast, mice deficient in all ?? T cells are phenotypically normal, and the sum of our findings suggests that interactions between ?? T cell subsets determine early T cell differentiation into IL-4 competent cell-types, and eventually overall (background) IL-4 production in non-immunized mice. Moreover, we see a positive correlation between high background IL-4 and much stronger IgE responses following immunization. Here, we propose to investigate the cellular interactions that determine the IL-4 baseline. To probe crosstalk among ?? T cells and between ?? and ?? T cells, we will change it, by manipulating individual T cell subsets through genetic knockout, specific antibody treatment or cell transfer, and then analyze the effect on the remaining cells using multi-parameter flow cytometry and high-dimensional data processing, to test the hypothesis that crosstalk among ?? T cells and between ?? and ?? T cells in thymus and periphery determine the extent of innate IL-4 production and IL-4-driven immune responsiveness in normal healthy mice. We suspect that similar pre-immune mechanisms are operational in humans. Knowledge about how the IL-4 baseline is established might enable its manipulation, and the adjustment of immune responsiveness towards healthy levels.
Immune protection against infectious pathogens and other immune functions rely in part on soluble mediators known as cytokines. Interleukin-4 (IL-4) is a cytokine that enables some of these healthy functions but also can have pathological effects. The proposed experiments are designed to further elucidate the mechanism by which IL-4 production is naturally regulated, and the new information obtained is expected to be helpful in controlling levels of this cytokine in clinical conditions where it can have pathological effects.
| 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 |
| Born, Willi K; Huang, Yafei; Reinhardt, R Lee et al. (2017) ?? T Cells and B Cells. Adv Immunol 134:1-45 |
| Born, Willi K; Huang, Yafei; Zeng, Wanjiang et al. (2016) A Special Connection between ?? T Cells and Natural Antibodies? Arch Immunol Ther Exp (Warsz) 64:455-462 |
