UNDERSTANDING THE ADAPTIVE IMMUNE RESPONSE: INTRACELLULAR PATHOGENS

摘要

The adaptive immune response to pathogens is a complex process and can follow many different pathways. In general, the cytotoxic T lymphocyte (CTL) response, also known as the CD8~+ T cell response, is directed toward intracellular pathogens includingviruses, intracellular bacteria, and some protozoa and fungi. Organisms that infect macrophages are a special case and will be discussed below. First we will discuss viral infection as the prototypical intracellular infection and highlight differences with other types of intracellular infection. Viral entry into host cells signals the cells to produce Type I interferons (IFNs), including IFN-alpha and IFN-beta, which act in an autocrine and paracrine fashion. At the same time, plasmacytoid dendritic cells (DCs) also begin to make massive amounts of Type I IFNs. These early events help to shape the entire downstream immune response, directing the response toward elimination of intracellular organisms. Type I interferons induce resistance to viral replication, promote display of cell surface markers recognized by natural killer (NK) cells, and activate NK cells which act as an early defense against intracellular infections. As the name implies, NK cells recognize virus-infected cells by alterations insurface receptors such as down-regulation of non-classical MHC-I molecules, which inhibit NK cell killing, and upregulation of NK stimulatory molecules such as MIC and CD48 to induce killing of the target cell. Natural killer cells produce large amountsof interferon-gamma (IFN-gamma, a Type II interferon) which activates antigen presenting cells such as macrophages and dendritic cells, thus initiating the adaptive immune response. In the local lymph tissue, antigen presenting cells (APCs), such as dendritic cells, begin presenting viral antigen via MHC I and MHC II which interact with the T cell receptor (TCR) on the CD8+ T cell surface and CD4+ T cell surface, respectively. Engagement of the TCR along with co-stimulatory signals from the APC leads toactivation of virus specific CD8+ CTLs and CD4+ T helper (Th) cells. At the same time, B cells internalize antigen via their B cell receptor, activating the B cell to present antigen to Th cells via MHC II and to differentiate into antibody producing plasma cells.Once activated, the CTL is able to then kill virus infected cells, one after another, utilizing a variety of mechanisms. First, the virus-infected cells must present viral antigen via MHC I. The CTL then engages the virus-infected cell through its TCR, recognizing the viral antigen / MHC I complex. This interaction creates an "immunologic synapse" and the activated CTL reorganizes its cytoskeleton to direct cytotoxic contents toward the target cell. CTLs contain cytotoxic granules that store cytotoxic proteins including perforin, granzyme, and granulysin. Perforin secreted by the CTL acts by forming a pore in the target cell membrane. This allows the toxic proteins granzyme and granulysin to enter the cell and induce apoptosis, without damaging neighboring, uninfected cells. CTLs are also able to activate cell surface receptors on the virus infected target cell that induce target cell death. Finally, activated CTLs secrete a variety of potent antiviral cytokines such as IFN-y and lymphotoxin that stimulate other lymphocytes and induce an "anti-viral state" in neighboring uninfected cells. At the same time, plasma cells have differentiated to produce antibody that neutralizes virus as virus particles are released from infected cells. The combination of a robust CTL response combined with the production of antibody leads to elimination of the infectious organism, or if the organism escapes the acute phase, establishment of a persistent infection.