Antigen-specific T cells are important sources of interferon (IFN)–γ for acquired immunity to intracellular pathogens, but they can also produce IFN-γ directly via a “bystander” activation pathway in response to proinflammatory cytokines. We investigated the in vivo role of cytokine- versus antigen-mediated T cell activation in resistance to the pathogenic bacterium Burkholderia pseudomallei. IFN-γ, interleukin (IL)–12, and IL-18 were essential for initial bacterial control in infected mice. B. pseudomallei infection rapidly generated a potent IFN-γ response from natural killer (NK) cells, NK T cells, conventional T cells, and other cell types within 16 h after infection, in an IL-12– and IL-18–dependent manner. However, early T cell– and NK cell–derived IFN-γ responses were functionally redundant in cell depletion studies, with IFN-γ produced by other cell types, such as major histocompatibility complex class II^int F4/80⁺ macrophages being sufficient for initial resistance. In contrast, B. pseudomallei–specific CD4⁺ T cells played an important role during the later stage of infection. Thus, the T cell response to primary B. pseudomallei infection is biphasic, an early cytokine-induced phase in which T cells appear to be functionally redundant for initial bacterial clearance, followed by a later antigen-induced phase in which B. pseudomallei–specific T cells, in particular CD4⁺ T cells, are important for host resistance