Certain intravesicular bacteria, including some mycobacteria and Listeria monocytogenes, escape from phagocytic vesicles and enter the cytoplasm, where they are no longer susceptible to the microbicidal actions of activated macrophages. Their presence can, however, be detected by cytotoxic CD8 T cells. The pathogens released when macrophages are killed by these CTLs can be killed in the extracellular environment by antibody-mediated mechanisms, or can be phagocytosed by freshly recruited macrophages. In this circumstance, the provision of TH1-mediated ‘help’ for the development of CTLs, such as the provision of IL-2, may play an important role in coordinating the TH1 and CTL responses.
Fig. 11.12 The immune response to intracellular bacteria is differrentiation and potentiates the release of other cytokines. IL-3 coordinated by activated TH1 cells. The activation of TH1 cells and GM-CSF stimulate the production of new monocytes by acting by infected macrophages results in the synthesis of cytokines that on hematopoietic stem cells in the bone marrow. New macrophages both induce M1 macrophage and coordinate the immune response are recruited to the site of infection by the actions of secreted to intracellular pathogens. IFN-γ and CD40 ligand synergize in TNF-α, LT-α, and other cytokines on vascular endothelium, which activating the macrophage, which allows it to kill engulfed pathogens. signal monocytes to leave the bloodstream and enter the tissues Chronically infected macrophages lose the ability to kill intracellular where they become macrophages. A chemokine with monocyte bacteria, and membrane-bound Fas ligand or LT-β produced by chemotactic activity (CCL2) signals monocytes to migrate into sites the TH1 cell can kill these macrophages, releasing the engulfed of infection and accumulate there. Thus, the TH1 cell coordinates bacteria, which are taken up and killed by fresh macrophages. In a macrophage response that is highly effective in destroying this way, IFN-γ and LT-β synergize in the removal of intracellular intracellular infectious agents. bacteria. IL-2 produced by TH1 cells augments effector T-cell 11-6 Activation of macrophages by TH1 cells must be tightly regulated to avoid tissue damage.
As discussed in Chapter 9, distinguishing features of effector T cells are their capacity for antigen-induced activation of effector functions without the requirement for co-stimulation, and also their efficient delivery of effector molecules through polarized secretion or expression of cytokines and cell-surface molecules—often through formation of an immunological synapse with an antigen-bearing cell (see Section 9-25). After a TH1 cell recognizes its cognate antigen expressed by a macrophage, the secretion of effector molecules requires several hours. TH1 cells must therefore adhere to their target cells far longer than do cytotoxic CD8 T cells. Similarly to cytotoxic T cells, the secretory machinery of the TH1 cell becomes oriented toward the site of contact with the macrophage and newly synthesized cytokines are secreted there (see Fig. 9.38). CD40 ligand also seems to be delivered to the same contact site. So although all macrophages have receptors for IFN-γ, the infected macrophage that presents antigen to the TH1 cell is far more likely to become activated than nearby uninfected macrophages.