Pulmonary infection by Yersinia pestis causes pneumonic plague, a rapidly 
progressing and often fatal disease. To aid the development of safe and 
effective pneumonic plague vaccines, we are deciphering mechanisms used by the 
immune system to protect against lethal pulmonary Y. pestis infection. In murine 
pneumonic plague models, passive transfer of convalescent-phase sera confers 
protection, as does active vaccination with live Y. pestis. Here, we demonstrate 
that protection by either protocol relies upon both gamma interferon (IFN-gamma) 
and tumor necrosis factor alpha (TNF-alpha) cytokines classically associated 
with type 1 cellular immunity. In both protocols, abrogating IFN-gamma or 
TNF-alpha activity significantly decreases survival and increases the bacterial 
burden in pulmonary, splenic, and hepatic tissues. Neutralization of either 
cytokine also counteracts challenge-induced, vaccination-dependent upregulation 
of nitric oxide synthase 2 (NOS2). Moreover, genetic depletion of NOS2 
suppresses protection conferred by serotherapy. We conclude that IFN-gamma, 
TNF-alpha, and NOS2, key elements of cellular immunity, perform critical 
protective functions during humoral defense against lethal pulmonary Y. pestis 
challenge. These observations strongly suggest that plague vaccines should 
strive to maximally prime both cellular and humoral immunity.