LYMPHOCYTES AND CELL-MEDIATED IMMUNITY
Lymphocytes play a significant role as effector cells in three main types of situations, all of them considered as expression of cell-mediated immunity, i.e., immune reactions in which T lymphocytes are the predominant effector cells.
Viruses, bacteria, parasites, and fungi have developed strategies that allow them to survive inside phagocytic cells or cells of other types. Infected cells are generally not amenable to destruction by phagocytosis or complement-mediated lysis. The study of how the immune system recognizes and eliminates infected cells resulted in the definition of the biological role of the histocompatibility antigens (HLA) that had been described as responsible for graft rejection . Those membrane molecules have a peptide-binding pouch that needs to be occupied with peptides derived from either endogenous or exogenous proteins. The immune system does not recognize self-peptides associated with self-HLA molecules. In the case of infected cells, peptides split from microbial proteins synthesized by the in-fected cell as part of the microbial replication cycle become associated with HLA molecules. The HLA-peptide complexes are presented to the immune system and activate specific cytotoxic T lymphocytes as well as specific TH1 lymphocytes. Both cytotoxic T cells and TH1 lymphocytes can mediate killing of the infected cells against which they be-came sensitized. Cytotoxic T cells kill the infected cells directly, stopping the replication of the intracellular organism, while activated TH1 cells release cytokines, such as inter-feron-γ , which activate macrophages and increase their ability to destroy the intracellular infectious agents.
As stated above, the immune system does not respond (i.e., is tolerant) to self-antigens, in-cluding antigens of the major histocompatibility complex (MHC), which includes the HLA molecules. However, transplantation of tissues among genetically different individuals of the same species or across species is followed by rejection of the grafted organs or tissues. The rejection reaction is triggered by the presentation of peptides generated from nonself MHC molecules. The MHC system is highly polymorphic (hundreds of alleles have been defined and new ones are added on a regular basis to the known repertoire), and this leads to the generation of millions of peptides, which differ in structure from individual to indi-vidual.
While the elimination of intracellular infectious agents can be considered as the main phys-iological role of cell-mediated immunity and graft rejection is an unexpected and undesir-able consequence of a medical procedure, other lymphocyte-mediated immune reactions can be considered as pathological conditions arising spontaneously in predisposed individ-uals. The most common example involves skin reactions, or cutaneous hypersensitivity, in-duced by direct skin contact or by intradermal injection of antigenic substances. These re-actions express themselves 24–48 hours after exposure to an antigen to which the patient had been previously sensitized, and because of this timing factor received the designation of delayed hypersensitivity reactions.