Regulatory interactions between two innate immune cells - iNKT and MZB cells - suppress autoimmunity (128.24)

Abstract

Abstract In vivo activation of iNKT cells prevents autoimmune diseases such as lupus at least during early stages of disease development. Conversely, loss of iNKT cells in CD1d-KO mice worsens nephritis in lupus-prone BWF1 mice. Mechanisms of regulation of autoimmunity by iNKT cells remain poorly understood. Here, using a variety of in vitro and in vivo experimental systems, including adoptive transfers in SCID and iNKT cell-deficient (Ja18–/–) mice, we demonstrate that although iNKT cells trans-activate B cells to increase expression of activation markers and production of normal Ig, they selectively suppress IgG autoantibody production. Whereas increased expression of B cell activation markers occurs via cytokines secreted by iNKT cells, iNKT cell-mediated suppression of IgG autoantibody production requires a direct contact between iNKT cells and B cells. Furthermore, although iNKT cells increase production of cytokines by other immune cells, they specifically inhibit IL-10 production by B cells in a contact-dependent manner. Furthermore, whereas iNKT cells increase activation markers on all B cell subsets including B1, B2 and marginal zone B (MZB) cells, they significantly reduce the MZB cell population in lupus-prone BWF1 mice. Further support for the role of iNKT cells in regulating MZB cells came from iNKT cell transgenic (Va14Tg) and deficient (Ja18–/–) mice. Whereas the proportion of MZ-B cells are increased in Ja18–/– mice as compared to wild type BALB/c mice, these cells are reduced in Va14Tg mice. Thus, iNKT cells suppress autoreactive B cells and prevent systemic autoimmunity. They do so via regulating MZ-B cells. Ongoing investigations will elucidate how activated iNKT cells activate MZB cells but reduce their IL-10 and autoantibody production.