An example of the importance of effector T-cell plasticity and cooperativity between subsets is found in host protection against facultative intracellular bacterial pathogens, such as Salmonella, which, unlike obligate extracellular bacteria, have also evolved mechanisms to survive within macrophages that are not activated by IFN-γ. Early in infection, Salmonella can colonize the intestinal epithelium similarly to other enteric Gram-negative pathogens. During this period, a TH17 response dominates, resulting in a robust IL-17induced influx of neutrophils that engulf extracellular bacteria and IL-22induced release of antimicrobial proteins that restrain bacterial growth in the intestinal lumen. During this intestinal phase of infection, much of the T-cell response appears to be directed against antigenic epitopes within bacterial flagellins, which are potent activators of TLR5. Activation of this innate sensor promotes IL-23 expression by CD11b+ classical dendritic cells in the intestine, and thereby induces a type 3 immune response. Flagellin-specific TH1cells also emerge during the early intestinal phase of infection, and may arise from TH17 cell precursors as a result of plasticity. To escape destruction by macrophages activated for intracellular killing by these ‘ex-TH17’ TH1 cells, Salmonella simultaneously downregulates the expression of flagellin and begins synthesizing new proteins, such as SseI and SseJ, that allow it to suppress intracellular killing within macrophages. This allows Salmonella to both evade detection by flagellin-specific T cells and use the host macrophage as a safe haven to shield it from extracellular killing—at least temporarily—as the infection spreads systemically.
During the systemic phase of the infection, the T-cell response shifts to become focused on those antigens that enable the intracellular lifestyle of the pathogen. Some of these newly expressed antigens appear to activate cytosolic sensors within CD8α+ classical dendritic cells, which produce IL-12 to activate pathogen-specific TH1 cells and a type 1 response. The pathogen can now be cleared by TH1-induced macrophage activation directed against these newly expressed antigens. Because the anti-pathogen response now includes both type 3 and type 1 immunity to different sets of antigens that the bacterium requires for its extracellular and intracellular lifestyles, Salmonella is deprived of a niche for its survival and is cleared from the host.
11-14 Integration of celland antibody-mediated immunity is critical for protection against many types of pathogens.
The type of effector T cell or antibody required for host protection depends on the infectious strategy and lifestyle of the pathogen. As we learned in Chapter 9, cytotoxic T cells are important in destroying virus-infected cells, and in some viral diseases they are the predominant class of lymphocytes present in the blood during a primary infection. Nevertheless, the role of antibodies in clearing viruses from the body and preventing them from establishing another infection can be essential. Ebola virus causes a hemorrhagic fever and is one of the most lethal viruses known, but patients who do survive are protected and asymptomatic if they become infected again. In both the initial and recurrent infection, a strong, rapid antiviral IgG response against the virus is essential for survival. The antibody response clears the virus from the bloodstream and gives the patient time to activate cytotoxic T cells. This antibody response does not occur in infections that prove fatal; the virus continues to replicate, and even though there is activation of T cells, the disease progresses.