The Role of Polarized Macrophages in LCMV Infection
Macrophages (MΦ) are a heterogeneous population of innate immune cells serving as the first line of defense during infection and as regulators of tissue homeostasis. During viral infections, MΦ rapidly sense infecting viruses to process and present antigen of major histocompatibility complex (MHC)-I for activation of virus specific CD8+ T cells. Moreover, through detection of pathogens and responding to environmental cytokines, monocytic derived bone marrow and peritoneal MΦ differentiate into polarized pro-inflammatory (M1) or anti-inflammatory (M2) states. However, little is known regarding the polarization capabilities of tissue resident MΦ, such as those of the spleen, which are of non-monocytic origin and how polarization influences CD8+ T cell immunity during viral infections. Therefore, we tested to what extent spleen derived (Sp)-MΦ polarize into M1 and M2 states and the functional consequences of polarization. We found that Sp-MΦ respond concordantly with bone marrow (BM)- MΦ to M1 stimulation to increase expression of iNOS and produce NO, or to M2 stimulation induce Arginase and Urea production. In addition, polarization impacted the phagocytic function of MΦ. Thus in this section, we established the novel polarization capabilities of polarized Sp-MΦ and the outcome on phagocytosis an important MΦ function. Next, we tested the MHC-I restricted antigen presenting abilities of polarized Sp-MΦ. To our surprise, we observed that M2 cells were proficient in inducing IFN-gamma secretion by effector CTL during peptide stimulation or following Lymphocytic Choriomeningitis Virus (LCMV) infection. However, M2 MΦ exhibit a deficiency in their ability to stimulate memory CD8+ T cell proliferation, which was reversed by additional IL-2. These findings highlighted previously unreported functions of polarized MΦ with regard to direct antigen presentation. Finally, we tested how virus priming into an in vivo M2 micro-environment influences subsequent CD8+ T cell immunity. In this study, we observed IL-4 pretreatment dramatically increased the quality of CD8+ T cell response enhanced viral clearance. The CD8+ T cell enhancement was prolonged into the memory phase of infection. Taken together, this thesis provides novel information regarding the polarization of tissue MΦ and how such polarization influences CD8+ T cell immunity and the outcome of viral infection.