Transcription factor profiling reveals activation of Type II Natural Killer T cell effector functions in response to Francisella tularensis infection.

Abstract

Abstract The bacterium Francisella tularensis (Ft) is the causative agent of human tularemia. When untreated, tularemia can reach a mortality rate as high as 30% in healthy adults with inhalation of as few as 10 colony forming units (CFU) inducing respiratory tularemia. While Ft is spread from zoonotic sources in nature, the ease of aerosol spread and high mortality in respiratory form led to its weaponization and concern for bioterrorism. Exposure to Ft elicits the cytokine storm, in which the immune system over-responds to the presence of the bacterium releasing massive amounts of proinflammatory and regulatory cytokines. Natural Killer T (NKT) cells are important immune cells that have both activating and inhibitory effector mechanisms. NKT cells are activated very early following Ft infection suggesting a critical role in the innate immune response to the bacterium. NKT cells are categorized into two distinct subsets based on their antigen recognition of CD1d-tetramers loaded with α-galactosylceramide (αGalCer-tetramer), though their individual characteristics in regulating inflammation are ill-defined. Type I NKT cells, similar to CD4+ αβ T helper cells, have been shown to express varied transcription factor (TF) profiles, e.g., T-bet, GATA3, and RORγT, contributing to either Th1, Th2 or Th17 phenotypes. It is not currently known whether this same TF profile classification exists within type II NKTs. The purpose of this research project is to investigate the activation of the type II NKT cell subset and characterize their TF profiles in response to Ft infection. This data will lead to a better understanding of the role of type II NKT cells in Francisella-mediated immunity. Supported by National Institute of General Medical Sciences (NIGMS) Research Initiative for Scientific Enhancement (RISE) grant R25 GM 06921-18