Macrophages play an essential role in antigen-specific immune suppression mediated by T CD8+ cell-derived exosomes

Abstract

Murine contact sensitivity (CS) reaction could be antigen-specifically regulated by T CD8+ suppressor (Ts) lymphocytes releasing microRNA-150 in antibody light-chain-coated exosomes that were formerly suggested to suppress CS through action on macrophages (Mϕ). The present studies investigated the role of Mϕ in Ts cell-exosome-mediated antigen-specific suppression as well as modulation of Mϕ antigen-presenting function in humoral and cellular immunity by suppressive exosomes. Mice depleted of Mϕ by clodronate liposomes could not be tolerized and did not produce suppressive exosomes. Moreover, isolated T effector lymphocytes transferring CS were suppressed by exosomes only in the presence of Mϕ, demonstrating the substantial role of Mϕ in the generation and action of Ts cell regulatory exosomes. Further, significant decrease of number of splenic B cells producing trinitrophenyl (TNP) -specific antibodies with the alteration of the ratio of serum titres of IgM to IgG was observed in recipients of exosome-treated, antigen-pulsed Mϕ and the significant suppression of CS was demonstrated in recipients of exosome-treated, TNP-conjugated Mϕ. Additionally, exosome-pulsed, TNP-conjugated Mϕ mediated suppression of CS in mice pre-treated with a low-dose of cyclophosphamide, suggesting de novo induction of T regulatory (Treg) lymphocytes. Treg cell involvement in the effector phase of the studied suppression mechanism was proved by unsuccessful tolerization of DEREG mice depleted of Treg lymphocytes. Furthermore, the inhibition of proliferation of CS effector cells cultured with exosome-treated Mϕ in a transmembrane manner was observed. Our results demonstrated the essential role of Mϕ in antigen-specific immune suppression mediated by Ts cell-derived exosomes and realized by induction of Treg lymphocytes and inhibition of T effector cell proliferation.