Exploring The Multiple Functions Of Neutrophils

Abstract

Neutrophils are one of the most effective antimicrobial cells in the innate immune system. They arrive at a site of infection or inflammation in response to a chemotactic gradient. At this site, they phagocytose invading pathogens and aid in their destruction through both oxidative and non-oxidative mechanisms. This is known to be mediated through the release of toxic granule contents and antimicrobial effector proteins. After their antimicrobial activity is perfo rmed, neutrophils undergo a programmed cell death process known as apoptosis and are quickly cleared from sites of inflammation by phagocytes. As such, neutrophils are believed to be fast acting, short-living effector cells that perform antimicrobial activities with limited influence on ensuing immune responses. Nevertheless, neutrophils are increasingly being shown to be regulators of adaptive immune responses. I show that neutrophils can act as professional antigen presenting cells capable of processing and presenting antigen to T cells. I also show that acquisition of antigen presentation ability is T cell-contact dependent and that the resulting T cell response is skewed towards a Th1 and Th17 phenotype. Neutrophils also have the ability to undergo a cell death process termed NETosis in which they extrude extracellular DNA that can trap and kill pathogens. I show that both mouse and human neutrophils undergo NETosis in response to the protozoan parasite Toxoplasma gondii and that the resulting entrapment leads to parasite killing. NETosis in response to Toxoplasma is parasiteinvasion independent and is mediated partly by signaling through the ERK pathway. The in vivo role of neutrophils during a Toxoplasma infection was also addressed. I show that neutrophil depleted and infected mice succumb to infection with highly dysregulated pulmonary immune responses. Depletion of neutrophils led to an increased phagocyte inflammatory state that resulted in an increase in T cell activity and cytokine production leading to pathology and ultimately death of the host. Data presented in this thesis challenge the traditional view of neutrophils and portray them more as immunoregulatory cells that can influence, shape, and regulate an immune response well beyond the stages of innate immunity and even beyond their own death.