The adaptive and innate arms of the immune system coordinate to respond to a secondary infection, resulting in both antigen-specific bactericidal activities and 'bystander' killing of unrelated pathogens, according to a recent report in The Journal of Experimental Medicine (204, 2075–2087).
After a foreign pathogen is encountered in an initial infection or vaccination, long-lived immunological memory is believed to be primarily in the hands of memory T cells. Once re-exposed to that pathogen, the armed memory CD8+ T cells quickly mount their killing campaign against infected cells. In an antigen-specific process, they release interferon (IFN)-γ and tumor necrosis factor (TNF)-α to control the growth and clearance of the pathogen. CD8+ T cells were thought to manage this process independently.
Emilie Narni-Mancinelli et al. have challenged this concept by demonstrating that the response to secondary infection is not solely dependent on memory T cells. Instead, activation of innate mononuclear phagocytic cells (MPCs) by the memory T cells is the necessary step for the final elimination of bacteria.
Upon re-exposure to the pathogen, existing memory T cells released the chemokine CCL3 to activate MPCs. MPCs released TNF-α, which in turn caused neutrophils and other MPCs to produce radical oxygen intermediates (ROIs) to clear the bacteria. The memory T cells by themselves were not sufficient to clear the infection, and blocking CCL3, TNF-α or ROIs prevented bacterial clearance.
Interestingly, an unrelated pathogen that is sensitive to ROIs was also cleared following the activation of innate cells during the secondary infection. When mice were immunized with bacteria and infected with another ROI-sensitive parasite, the mice cleared the remaining bystander parasite effectively during the secondary bacterial infection.
These findings have a number of clinical applications. For instance, in the past, measurements of TNF-α and IFN-γ have been used to determine vaccine efficacy. This work suggests that CCL3, the crucial link for MPC activation and ROI production, could be a superior readout, because it better represents the activity of memory T cells. This knowledge could also change the way we think about vaccinations. Memory responses could be manipulated to eliminate microbes that have developed resistance to multiple drugs, such as Mycobacterium tuberculosis and Staphylococcus aureus. Perhaps the triggering of memory T cells specific to a previously received, unrelated pathogen could be used to activate ROI-producing MPCs to clear these or other new infections.
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Jeffrey, K. Rechallenging immunological memory. Nat Med 13, 1142 (2007). https://doi.org/10.1038/nm1007-1142a
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