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

NK cells are part of the cellular innate immune response and recent work established their key role in host specific control of a primary ECTV infection [51, 52] . Interestingly, we found here that depletion of NK cells did not influence the rapid protective capacity of MVA vaccination. This observation already indicated differences in the modes of immune defense when comparing rapidly protective primary immunization, protection against secondary infection, and overcoming a primary ECTV infection. This latter scenario is well characterized in C57BL/6 mice that resist foot-pad infections known to be lethal in more susceptible mouse strains. This primary resistance was shown to mainly depend on the presence of NK cells and T cells. Nevertheless, B cells are essential for complete virus clearance and recovery [50, 52, 72, 73] . In contrast, protective immunity against secondary infections, elicited by primary infection or conventional vaccination, is dominated by antibody responses [23, 27, 40, [74] [75] [76] . Recovery from secondary ECTV infection was demonstrated to rely on a more rapid recall antibody response than in primary infection, whereas secondary recall CTL responses were not altered compared to primary CTL responses [77] . Nevertheless, memory CD8+ T cells are known to prevent viral spread by killing viral targets in the draining lymph nodes and thus are also important in controlling secondary ECTV infections [78] . Thus, the antibody memory response seems to be mandatory for longterm protective immunity against orthopoxvirus infections especially in controlling virus persistence while T cell responses might be more important to prevent viral spread.