- Cell-mediated Immunity is the arm of the Adaptive Immune Response which results in the generation of antigen-specific effector T-cells. A variety of effector T-cells sub-types are generated during an Adaptive Response and are responsible for either direct killing of infected cells or induction of effector functions by other immune cells. Here we outline the steps of Adaptive Immunity and organize this section according to the "Basic Architecture" of the Adaptive Immune Response (see page).
|Random Generation and Selection|
- The random generation and selection of large numbers of T-cells which express a unique antigen-specific T-cell Receptor that cannot recognize self-peptides is described more fully in T-cell Development. The end result of these stages is a large pool of peripheral T-cells which continuously circulate through the blood and lymph nodes waiting to encounter a peptide:MHC complex which is recognized by their T-cell Receptor. Importantly, two subtypes of T-cells are generated following these processes: CD8+ T-cells which recognize peptide displayed on MHC I and CD4+ T-cell]s which can recognize peptide displayed on MHC II.
|Proliferation and Differentiation|
- T-cells require two basic stimuli to undergo proliferation: 1) A peptide:MHC complex which is recognized by their[T-cell Receptor, and 2) The presence of certain co-stimulatory molecules. Given these two inputs, the basic sequence for activation is the same for CD4+ T-cells and CD8+ T-cells; however, once activated, the effector functions of these two cell types are vastly different as described below.
- Encounter with Peptide:MHC
- Naive, mature T-cells encounter peptide:MHC complexes as they circulate through the Paracortex of lymph nodes (See: Lymph Node Histology). The source of peptide:MHC complexes are Antigen Presenting Cells (APCs), such as Dendritic Cells and Macrophages. Recall that APCs phagocytose material in local tissues, degrade it, and display the resultant peptides on MHC II, after which they migrate to local lymph nodes where they can encounter naive T-cells. In addition to their presentation function, APCs provide critical context regarding the displayed peptides by determining whether they are microbial in origin or derived from normal host cellular debris.
- APCs distinguish microbial from host debris using "Pattern Recognition Receptors (PRRs)" described more fully in the Innate Immune Response. If the APCs PRRs are activated, the APC will also express the critical co-stimulatory molecule B7 on its surface, indicating that the displayed peptides are microbial in origin. If the APCs PRRs are not activated, the APC will not express B7, indicating that the displayed peptides originate from host cells. T-cell proliferation requires both stimulation of the T-cell Receptor along with activation of the co-receptor, CD28, which is ligated by the APC co-stimulatory molecule B7. The co-stimulation requirement for T-cell proliferation likely evolved to ensure that any self-reacting T-cells which may have escaped negative selection are not inappropriately activated by host peptides presented on Antigen Presenting Cells.
- Proliferation of naive, mature T-cells is ultimately dependent on stimulation with IL-2 which is the master regulator of T-cell proliferation. Interestingly, the IL-2 is secreted by the T-cell itself and is synthesized, along with IL-2-receptor, following engagement of T-cell CD28 by APC B7. Consequently, activation of the IL-2 autocrine loop is the mechanistic basis of the co-stimulatory requirement for T-cell proliferation.
- Following proliferation, the T-cells differentiate into effector cells with the properties described in the next section. CD8+ T-cells differentiate into Cytotoxic CD8+ T-cells while CD4+ T-cell]s differentiate into Th1 or Th2 effector subtypes. Depending on the microbe, the immune response will skew differentiation of CD4+ T-cells in the direction of Th1 Cells or Th2 Cells and it is not clear how this skewing is determined. It is thought that APCs coordinate this skewing likely based on signals which suggest that the organism may be extracellular or intracellular. Extracellular organisms produce a Th2-response which promotes antibody formation whereas intracellular organisms produce a Th1 response.
- The common feature of all effector T-cells is that upon encounter of a cell displaying a recognizable peptide:MHC complex, the effector T-cell showers the cell with proteins that induce different responses. In the case of Cytotoxic CD8+ T-cells the secreted proteins kill the target cell. In the case of Th1 Cells the secreted proteins stimulate the target cell to kill internalized microbes. In the case of Th2 Cells the secreted proteins induce the target cell to proliferate.
- Cytotoxic CD8+ T-cells
- Once generated, Cytotoxic CD8+ T-cells migrate throughout the body's tissues searching for cells which display peptide:MHC I complexes that their T-cell Receptor recognizes. Because the peptides displayed on MHC I are derived from degradation of cytosolic proteins, recognition of microbial peptide on the cell's MHC I indicates that the cell is infected. The response of the CD8+ T-cell is to release a variety of cytotoxic molecules which kill the target cell. Consequently, Cytotoxic CD8+ T-cells are critical for elimination of cytosolic microbes such as viruses and certain bacteria which proliferate in the cytosol.
- Th1 Cells
- CD4+ T-cells of the Th1 subtype migrate through host tissues and recognize microbial peptide:MHC II complexes displayed on macrophages. In general, these are macrophages which have phagocytosed a microbe but have not completely killed the organisms within their phagosomes. When such macrophages are encountered, Th1 Cells shower the macrophages with Interferon-gamma which substantially enhances the microbe-killing capacity of their phagosomes. This enhancement occurs by increased production of phagosomal Reactive Oxygen Species and delivery of toxic proteases to the phagosome. It is thought that macrophages require this additional Th1-mediated stimulus because inappropriate generation of these Reactive Oxygen Species and proteases can be extremely harmful to host tissues. Thus, Th1 Cells are critical for elimination of Facultative Intracellular bacteria which survive and proliferate in macrophage phagosomes.
- Th2 Cells
- CD4+ T-cell]s of the Th2 subtype migrate to lymph nodes where they sample activated B-cells that are displaying microbial peptide:MHC II complexes on their surface. As described in Humoral Immunity these are B-cells which have internalized a microbe using their B-cell Receptor, degraded the organism, and are now displaying the resultant peptides using MHC II. These activated B-cells require additional stimuli to proliferate and differentiate into effector cells of Humoral Immunity. Upon encountering B-cells displaying recognizable peptide:MHC II complexes on their surface, Th2 Cells shower the B-cells with cytokines such as IL-4 and IL-5 which induce the B-cell to proliferate and differentiate into antibody secreting cells. Th2 Cells also appear to be critical for successful isotype switching in B-cells as described in Humoral Immunity.
- The mechanisms and cellular basis of Cell-mediated memory is currently not well-understood. Following clearance of an infection, antigen-specific CD4+ and CD8+ effector T-cells drop in number but a small population is usually maintained for years afterwards. It is likely that these are the Memory T-cells which form the basis of Cell-mediated memory; however, a detailed understanding of these cells is still lacking. Whatever the case, re-infection with a microbe results in a much more rapid and profound proliferation of effector T-cells which allows brisk clearance of the organism.