THE PROTECTIVE ROLE OF CELL-MEDIATED IMMUNITY
Many organisms have the ability to grow and replicate intracellularly, some as an absolute requirement, others as an option that allows them to survive after phagocytosis. Antibodies are largely ineffective against such organisms, and T lymphocytes play a major role in their elimination, as reflected by the finding of lymphocytic infiltrates in tissues infected by in-tracellular infectious agents, such as viruses. The immune system has two basic options to eliminate those organisms: to kill the infected cell or to enhance the infected cell’s ability to kill intracellular organisms. Either option requires the persistent activation of the TH1 subpopulation of helper cells.
This process is particularly significant for the elimination of virus-infected cells. It can be easily demonstrated that virus-infected cells are lysed as a consequence of their incubation with “immune” lymphocytes obtained from an animal previously exposed to the same virus. The sequence of events involves recognition of virus-derived peptides expressed in association with MHC-I molecules by CD8+ lymphocytes followed by differentiation into cytotoxic T cells specific for the same MHC-I/peptide complex that they recognized when initially activated. The differentiation may be TH-independent if large amounts of IL-2 are released by CD8+ cells, which can induce autocrine differentiation, but it usually requires TH1 help. The activation of TH1 cells usually requires recognition of MHC-II/peptide com-plexes. Considering that macrophages are common targets for most viral infections, they are likely to present viral peptides associated with both MHC-I and MHC-II molecules. This duality should allow the simultaneous activation of CD4+ and CD8+ T cells in close proximity, an ideal set-up for delivery of “help” to activated precursors of cytotoxic T cells.
Most intracellular bacteria and parasites infect tissue macrophages and fail to induce effi-cient cytotoxic reactivity. The persistence of the infection depends on a delicate balance be-tween a state of relative inactivity by the macrophage and mechanisms that allow the in-fectious agent to escape proteolytic digestion once inside the cytoplasm . The immune system can react through a humoral response, which is largely ineffective, or through a TH1-mediated inflammatory response, which may actually induce the elimina-tion of the pathogen.
The effective response involves activation of CD4+ TH1 lymphocytes as a conse-quence of their interaction with infected macrophages expressing MHC-II–associated pep-tides and releasing IL-12. The role of IL-12 appears to be critical, because IL-12 receptor deficiency is associated with the predisposition to develop tuberculosis, a classical exam-ple of intracellular infection. When properly activated by IL-12, TH1 lymphocytes release a variety of lymphokines, particularly interferon-γ , which activates macrophages, enhanc-ing their ability to kill intracellular organisms , and GM-CSF, which pro-motes differentiation and release of granulocytes and monocytes from the bone marrow. As a consequence of the delivery of activation signals, macrophages and lymphocytes enter a complex cycle of self and mutual activation involving a variety of cytokines. In addition, several of these cytokines may activate other types of cells known as chemotactic cytokines or chemokines . This group of cytokines includes interleukin-8 (IL-8), RANTES, macrophage inflammatory proteins (MIP), macrophage chemotactic proteins (MCP), migration-inhibition factor (MIF), and β-defensins. Collectively the chemokines attract and activate leukocytes and keep them in the area where a cell-mediated immune re-action is taking place.
In concert with the release of chemotactic cytokines, the expression of CAMs in neighboring microvasculature is upregulated, favoring adherence and migration of mono- cytes and granulocytes to the extravascular space. Inflammatory cells accumulate in the area of infection, and as a consequence of cross-activation circuits involving phagocytes and TH1 lymphocytes, the localized macrophages and granulocytes become activated. As a consequence, the enzymatic contents and respiratory burst of the cells become more in-tense, making them better suited for killing intracellular organisms, phagocytosis is en-hanced, and the activated macrophages release higher levels of cytokines. The cytokines re-leased by activated macrophages include IL-12, which continues to promote the differentiation of TH1 cells, as well as IL-1, IL-6, and TNF, which in association with IL-8 play a major role in inducing the metabolic effects characteristic of the inflammatory re-action .