Co-stimulatory receptors CD28 and CTLA4 are required for optimal NK cell effector function and memory formation during MCMV infection (168.3)

Abstract

Abstract Natural Killer (NK) cells are generally classified as a component of the innate immune system. However, recent evidence in mice and humans suggests that NK cells have properties of both innate and adaptive immunity. Optimal T cell activation requires both T cell receptor ligation, a co-stimulatory signal provided by CD28, and regulation by the inhibitory receptor CTLA-4. Although NK cells have been shown to express CD28, the importance of co-stimulation in NK cell responses in vivo has not been previously investigated. Using mice deficient in CD28, and receptor-blocking antibodies, we investigated the role of this receptor on NK cells using a mouse model of cytomegalovirus (MCMV) infection. After primary infection with MCMV, we found that CD28 is necessary for early viral control of MCMV by antigen-specific Ly49H+ NK cells and consequently memory NK cell formation. In addition, we have new evidence that CTLA-4 is highly expressed on activated NK cells during MCMV infection. Surprisingly, like CD28, expression of CTLA-4 was also required for optimal proliferation and function of Ly49H+ NK cells during MCMV infection. Manipulation of these co-stimulatory signals within the immune system is an emerging strategy of effective vaccination and tumor therapy. Therefore, understanding the molecular mechanisms behind effective NK cell responses to pathogens will be critical in our attempts to modulate the immune system against these ailments.