Human mast cells present antigen to autologous CD4+ T cells

Background: Mast cells (MCs), the primary effector cell of the atopic response, participate in immune defense at host/environment interfaces, yet the mechanisms by which they interact with CD4(+) T cells has been controversial. Objective: We used in situ matured primary human MCs and matched CD4(+) T cells to diligently assess the ability of MCs to act as antigen-presenting cells. Methods: We examined mature human skin-derived MCs using flow cytometry for expression of antigen-presenting molecules, for their ability to stimulate CD4(+) T cells to express CD25 and proliferate when exposed to superantigen or to cytomegalovirus (CMV) antigen using matched T cells and MCs from CMV-seropositive or CMV-seronegative donors, and for antigen uptake. Subcellular localization of antigen, HLA molecules, and tryptase was analyzed by using structured illumination microscopy. Results: Our data show that IFN-gamma induces HLA class II, HLA-DM, CD80, and CD40 expression on MCs, whereas MCs take up soluble and particulate antigens in an IFN-gamma independent manner. IFN-gamma primed MCs guide activation of T cells by Staphylococcus aureus superantigen and, when preincubated with CMV antigens, induce a recall CD4(+) T(H)1 proliferation response only in CMV-seropositive donors. MCs co-opt their secretory granules for antigen processing and presentation. Consequently, MC degranulation increases surface delivery of HLA class II/peptide, further enhancing stimulation of T-cell proliferation. Conclusions: IFN-gamma primes human MCs to activate T cells through superantigen and to present CMV antigen to T(H)1 cells, co-opting MC secretory granules for antigen processing and presentation and creating a feed-forward loop of T-cell MC cross-activation.