Critical Role of Perforin-dependent CD8+ T Cell Immunity for Rapid Protective Vaccination in a Murine Model for Human Smallpox

Kremer, Melanie; Suezer, Yasemin; Volz, Asisa; Frenz, Theresa; Majzoub, Monir; Hanschmann, Kay-Martin; Lehmann, Michael H.; Kalinke, Ulrich; Sutter, Gerd

The present work was carried out in C57BL/6 mice deficient in various components of the innate or adaptive immune system, exposed to a lethal respiratory infection with ECTV administered two days after immunization. Immunization and challenge of normal C57BL/6 mice served as controls to determine the degree of protection, as monitored by disease symptoms, body weight loss and survival. Moreover, intranasal vaccination of fully immune competent mice allowed us to assess the quality and kinetics of immune responses elicited at the primary site of immunization. Previous studies had suggested that VACV and MVA are recognized via multiple host-sensing pathways, including TLRs, RLRs and NOD-like receptors (NLRs) [44, 64] . Furthermore, MVA infection induces pro-inflammatory cytokines such as TNFa [44, 65] , type I interferons [14, 47, 66] and chemokines like CCL2 that attract leucocytes to the site of inoculation [46] . At 24 to 48 hours after i.n. MVA inoculation we found prominent infiltrations of immune cells in the lungs of immunized mice. We also detected significantly increased amounts of the proinflammatory cytokines IL-6 and IFN-a in BAL fluids, which correlate with efficient activation of innate responses in the respiratory tract.