NK cell-mediated regulation of humoral immune responses during autoimmunity

ABSTRACT Systemic lupus erythematosus (SLE, lupus) is a devastating autoimmune disease driven by pathogenic autoantibodies that promote tissue injury. The autoantibodies are produced by dysregulated germinal center (GC) B cells and Age-associated B cells (ABCs) receiving inappropriate differentiation, survival, and proliferation signals from CD4+ T follicular helper (Tfh) cells. The molecular and cellular events that lead to lymphocyte dysregulation during lupus are complex and still not well understood. Emerging data suggest that Natural Killer (NK) cells, best known for their ability to kill infected and malignant cells, play important roles in restricting excessive Tfh cell and B cell responses during infection. In viral infections, depletion of NK cells has been shown to increase Tfh cells, GC B cells, and anti-viral antibodies. Whether NK cells regulate humoral responses during lupus remains unclear. However, circulating NK cells are dysfunctional and significantly reduced in SLE patients with active disease, and this reduction coincides with increases in circulating Tfh cells and B cells and elevated autoantibody titers. We hypothesize that NK cells are important negative regulators of pathogenic humoral responses during lupus, with specific roles in restricting disease-driving Tfh cell and B cell populations. Accordingly, we will dissect the effects of NK cell, Tfh cell, and B cell interactions on autoantibody production and disease progression during lupus. In Aim 1, we will investigate the role of NK cells in restricting Tfh cell, GC B cell and ABC responses at different stages of lupus disease in mice. Aim 2 will assess the direct cellular and molecular interactions that underlie NK cell-mediated regulating of humoral immune responses during lupus. Finally, Aim 3 will test novel therapeutic agents designed to promote NK cell-mediated killing of Tfh cells and B cells for potential therapeutic use in lupus. These studies are expected to critically advance our understanding of how NK cell dysfunction impacts pathogenic Tfh cell and B cell responses in autoimmunity. Ultimately, this information could provide new therapeutic targets to dampen adaptive immune responses in autoimmunity.