Adaptive Immunity - Cellular ResponseT cells are lymphocytes that directly or indirectly eradicate pathogens. They respond to intracellular targets, as opposed to the B cells of the humoral arm, which respond to extracellular microbes.T cell Life Cycle Origins: They arise from stem cells in the bone marrow. Maturation: T cells mature in the thymus (T is for Thymus): maturation involves positive and negative selection, and gives rise to naïve (non-activated) cells defined by the presence of either CD4 or CD8 proteins on their surfaces. Activation: In the secondary lymphoid organs, such as the lymph nodes and spleen, naïve T cells are activated by antigens; the naïve T cells become functional effector cells. Apoptosis: After the pathogen is eradicated, most of the effector cells undergo apoptosis; otherwise, they pose a potential danger to the host cells. Differentiation: Some of the T cells differentiate to become memory cells, which will respond if/when the host is exposed to the same antigen – thus, the secondary response to subsequent exposure can occur much faster. MHCMajor Histocompatibility Complex (MHC) molecules present peptide antigens that activate T-cells.Class I MHC molecules Present fragments of antigens that are synthesized endogenously – i.e., peptides derived from viral antigens produced within the cells. Class I MHC molecules are only recognized by naïve CD8+ T cells and their Cytotoxic T cell descendants.Class II MHC molecules Present fragments from extracellular microbes and pathogens – i.e., peptides derived from extracellular microbes. Class II MHC molecules are only recognized by naïve CD4+ T cells and their Helper T cell descendants. T Cell MaturationThymic education - two selective mechanisms that eliminate T cells that would otherwise harm the host: Positive selection ensures that the surviving T cells can recognize the MHC complex, which is necessary for their activation, while negative selection ensures that self-destructive T cells are eliminated.Positive selection Occurs in the thymic cortices Immature T cells are exposed to cortical epithelial cells displaying self-MHC complexes: The T cells that recognize the MHC complexes survive Those that fail to recognize the MHC complexes undergo apoptosis.Negative selection Occurs in the thymic medullaeT cells are exposed to MHC complexes with self-antigen: Those T cells that do NOT respond to the self-antigen survive The T cells that DO respond undergo apoptosis. T Cell Types: Ultimately, thymic maturation produces three main types of T cells, which we designate based on their unique cell surface proteins: CD8+, CD4+, and CD4+/CD25+.Regulatory T Cells CD4+/CD25+ T cells are Regulatory T cells; they can suppress the activity of the other T cell types via expression of Cytotoxic T Lymphocyte Antigen 4 (CTLA-4). T-Cell Receptors:: In addition to the CD proteins, naïve T cells also express receptors (T-Cell Receptors, TCRs) for specific antigens; binding with their specific antigen induces their activation. T Cell ActivationActivating Cells:MHC class I molecules are displayed by all nucleated cells (in other words, most body cells except red blood cells). MHC class II molecules are displayed by dendritic cells, macrophages, and B cells – because of this unique ability, these are referred to as "antigen-presenting cells." However, be aware that B cells do not activate naïve T cells; they stimulate mature Helper T cells as part of their own activation (discussed in detail, elsewhere). As we learned earlier, CD8+ and CD4+ T cells recognize different MHC classes; this means that they can only be activated by cells displaying the appropriate MHC molecules.An Activation Example: 1. An antigen-presenting cell, such as a dendritic cell, recognizes and engulfs a microbe. 2. It digests the microbe and re-packages a peptide fragment with an MHC class II molecule on its surface. 3. The MHC- antigen complex is recognized by a naïve CD4+ cell, which is subsequently activated. Notice that if the antigen-presenting cell displayed only antigens complexed with MHC class I molecules, the CD4+ cell would not have recognized it. Activating mechanisms in more detail:CD8+ T cell: 2-signal activation of a CD8+ T cell, which differentiates to become a cytotoxic cell. The cell surface of the CD8+ has the T-cell Receptor Complex (TCR complex), which consists of the following components: The T-cell receptor, which is specific to the peptide antigen displayed by the MHC molecule; CD3 proteins; and, the CD8 protein, which recognizes and interacts with the MHC class I molecule of the nucleated cell.The representative nucleated cell displays the class I MHC - antigen complex.The interaction between the TCR complex and nucleated cell allows for the second signal, which involves co-stimulation between CD28 and B7-2. Activation triggers proliferation, aka, cloning, of the T cell and differentiation into the effector type – which, for CD8+ cells, is the Cytotoxic T cell. These processes are guided by cytokines, which are released by T cells and antigen-presenting cells.CD4+ T cell: 2-signal activation of a CD4+ T cell, which differentiates to become a Helper T cell.The dendritic cell surface displays the MHC II-antigen complex.The CD4+ cell has the TCR complex: the T-cell receptor, which is specific to the antigen; the CD3 molecules; and, the CD4 protein that interacts with the MHC II molecule on the antigen-presenting cell.The second signal comprises co-stimulation: interaction between CD28 on the surface of the T cell and B7-2 on the dendritic cell. Activation results in proliferation and differentiation to effector cells. Effector Cell FunctionsCytotoxic T cells directly kill pathogen-bearing cells via the following steps: 1. The T cell recognizes the MHC I – antigen complex. 2. Docking brings the two cell membranes in close association. 3. The T cell releases perforins, which form a pore in the infected cell's membrane. 4. The cytotoxic cell releases granzymes, which move through the pore and trigger apoptosis of the infected cell.Helper T cells, the products of activated CD4+ cells, have multiple roles in both innate and adaptive responses: - They amplify the innate response via cytokine release and recruitment of neutrophils and macrophages. - They activate B cells, which mediate the humoral arm of the adaptive immune response. - They activate cytotoxic T cells, in part by upregulating the expression of co-stimulatory molecules on dendritic cells. - Superantigens, such as Staphylococcus bacteria, are super potent activators of CD4+ cells.4 subsets of Helper T cells: - Th1: develop under the influence of interferon-gamma and IL-12. Anti-viral activity, macrophage activation, and induce cytotoxic T cell differentiation; when unregulated, they are associated with autoimmune diseases. This subset produces IL-2 and interferon-gamma. - Th2: develop under the influence of IL-4. This subset is particularly important in defense against worms and in mobilization of eosinophils; they are associated with allergies and asthma. They produce IL-4, IL-5, and Il-13. - Th17: develop under influence of Tissue growth factor-beta, IL-6, IL-1, and IL-23. This subset recruit neutrophils and monocytes. They are also associated with autoimmune disease. They produce IL-17 and IL-22. - Follicular helper T cells: differentiation is thought to require interaction with B cells. Follicular helper T cells promote the humoral immune response and produce IL-21.