Mast cell activation enhances the TLR4-mediated antigen-specific CD4 T cell response

Abstract

Abstract Mast cells are important immune mediators located at host environment interfaces and are most well-known as the major mediators of allergy and asthma. When activated, they have the ability to release prestored granules that contain immune modulating compounds, such as histamine and inflammatory cytokines. In skin, mast cell activation happens via crosslinking of the high-affinity FcɛRI receptor which is activated by the antibody IgE on the mast cell surface binding to a pathogen or allergen inducing intracellular signaling. While there is some evidence that mast cell activation alone does not induce expansion of endogenous antigen-specific CD4 helper T cells, it is not clear whether mast cells have the capacity to fine tune the expansion of T cells that are responding to other stimuli. To assess this, we focused on determining the effects of mast cell activation through FcɛRI alone or in combination with bacterial products on the generation of antigen specific CD4 T cells. Using an in vivo skin model of mast cell activation, combined with MHC class II tetramers, we show that crosslinking FcɛRI alone does not induce antigen-specific CD4 T cell immunity; however, cross-linking FcɛRI in the presence of the Toll-like receptor 4 (TLR4) agonist LPS provides a synergistic co-stimulatory signal that significantly increases T cell expansion. This effect is lost when stimulating with CpG, a TLR9 agonist. We also show that this synergy is lost when dendritic cells are ablated prior to activation. Further, we demonstrate that TLR4 expression by the mast cells themselves is essential to maintain this synergy. This study provides insights into the ability of mast cells to alter antigen-specific CD4 T cell responses in vivo in response to inflammatory stimuli.