A. Cell-Mediated Immunity

 Within the adaptive immune response, the cooperative interaction of both antibody- and cell-mediated immunity provides the best opportunity for combating infection. In fact, effective antibody responses depend on the activation of T cells. This section directs attention to T-cell activation, T-cell recognition of antigen, and T-cell subsets and their function as well as T-cell development, proliferation, and differentiation.

1. Development of T cells—As previously mentioned, T cells are derived from the same hematopoietic stem cells as are the B cells. Within the thymus, T cells mature and undergo differentiation. Under the influence of thymic hormones, T cells differentiate into committed cells expressing a specific TCR. These T cells have undergone VDJ recombination of their β chain and then rearrangement of their α chains. Now these T cells undergo two processes: one positive and one negative. During positive selection, cells that recognize self-peptide plus self-MHC with weak affinity will survive. These cells are now termed self-MHC restricted. During negative selection, the cells that recognize self-peptide plus self-MHC with high affinity are killed. The survivor cells, CD4+ CD8+ double positive T cells, continue to mature into either CD4+ or CD8+ T cells. Only a minority of developing T cells express the appropriate receptors to be retained and enter the periphery where they

2. T-cell receptor for antigen—The TCR is the recognition molecule for T cells. The TCR is a transmembrane heterodimeric protein containing two disulfide-linked chains. It is composed of two different classes of TCR called: alpha beta (α and β) and gamma-delta (γ and δ). The majority of the T cells contain the αβ TCR phenotype. However, a smaller percentage of T cells express the γ δ TCR. The αβ T cells are subdivided by their surface markers: CD4 or CD8. Little is known about the activities of the γδT cells. The γδ T cells are primarily located in the epithelial linings of the reproductive and GI tracts.

The structure of the TCR resembles the Fab fragment of an immunoglobulin molecule; that is, the TCR has both variable and constant regions. More specifically, each chain has two extracellular domains: a variable region and a constant region. The constant region is closest to the cell mem brane, whereas the variable region binds the peptide–MHC complex. When the TCR engages the antigen peptide–MHC complex, a series of biochemical events occur. These are dis cussed later in the text.

As outlined for the immunoglobulins, the diversity of the TCR is similar to that described for the BCR. The α chain of the TCR is the result of VJ recombination, whereas the β chain is generated by VDJ recombination. These segments can combine randomly in different ways to generate the com plex TCR.

The TCR complex is formed by the highly variable α and β chains of the TCR plus the invariant CD3 proteins. The invariant proteins of the CD3 complex are responsible for transducing the signal received by the TCR when antigen recognition occurs. The different proteins of the CD3 complex are transmembrane proteins that can interact with cytosolic tyrosine kinases that initiate signal transduction leading to gene transcription, cell activation, and initiation of the functional activities of T cells.

In addition to the TCR complex, the T cell signal is also enhanced by the presence of coreceptors. The CD4 and CD8 molecules on the T cell membrane function as coreceptor molecules. During recognition of antigen, the CD4 and CD8 molecules interact with the TCR complex and with MHC molecules on the APC. CD4 binds to MHC class II molecules and CD8 binds to MHC class I molecules.

3. T-cell proliferation and differentiation—T-cell proliferation depends on a series of events. In MHC class II presentation, two signals are required for the naïve CD4 T cell activation to occur. The first signal comes from the TCR on the T cell interacting with an MHC–peptide complex presented on the APC. The CD4 glycoprotein on the naïve T cell acts as a coreceptor, binding to MHC class II molecules. This binding event helps ensure stability between the T cell and the APC. The second signal (costimulation) that is required for T-cell activation is derived from the interaction of the B7 family costimulatory molecules (B7-1/B7-2 also identified as CD80 and CD86) on the APC with CD28 on the T cell. These are the major costimulatory molecules. Upon completion of these two stimulation steps (eg, TCR binding to MHC class II–peptide complex and CD28 binding to B7-1/B7-2), a set of biochemical pathways are triggered in the cell that results in DNA synthesis and proliferation. During these events, the T cell secretes cytokines, mainly IL-2 and IFN-γ, and increases the expression of IL-2 receptors. These T cells are able to proliferate and differentiate into effector cells.

CD8 T-cell activation occurs when the TCR interacts with the MHC class I–peptide complex on the infected cell. The CD8 glycoprotein on the T cell acts as a coreceptor, binding to MHC class I molecule on the APC. Again, this interaction keeps the two cells bound together during antigen-specific activation. Once activated, the cytotoxic T cell produces IL-2 and IFN-γ, growth and differentiation factors for T cells. Unlike CD4 cell activation, CD8 T-cell activation in most cases is independent of costimulation, and the virus-infected cell is destroyed through cytotoxic granules released from the CD 8 T cell.

Because the immune system is highly regulated, it can also downregulated immune activation to limit overwhelming or excessive responses and hence avoid inadvertent damage to the host. The immune system is equipped with a checkpoint system and several negative regulatory check points, which perform this function. CTLA-4 and PD-1 are two cell surface receptors that can turn off activated T cells when they interact with their ligand. For example, CTLA-4 blocks signal 2 and therefore prevents T cell activation.

B. T-Cell Effector Functions

1. CD4 effector cells—Proliferating CD4 T cells can become one of five main categories of effector T cells: Th1cells, Th2 cells, Th17 cells, Tfh, or T regulatory (T reg) cells (Figure 1).

Fig1. CD4 T Cells: peptide + MHC class II. (Reproduced with permission from Murphy K, Weaver C: Janeway’s Immunobiology, 9th ed., Figure 9.30. Copyright © 2017 by Garland Science, Taylor & Francis Group, LLC. Used by permission of W. W. Norton & Company, Inc.)

Th1—Th1 cells are triggered by IL-2 and IL-12 and either activate macrophages or cause B cells to switch to produce different subclasses of IgG. In either case, this can promote bacterial clearance either by direct destruction in the IFN-γ–activated macrophage or by destruction after phagocytosis of opsonized particles. These Th1 cells also produce IL-2 and IFN-γ.

Th2—In an environment where IL-4 is being produced, Th2 cells predominate and activate mast cells and eosinophils and cause B cells to synthesize IgE. This aids in the response to helminths. The Th2 cells secrete IL-4, IL-5, IL-9, and IL-13.

Th17—When TGF-β, IL-6, and IL-23 are present CD4 T cells can become Th17 cells. These cells produce IL-17, IL-21, and IL-22. IL-17 is a cytokine that induces stromal and epithelial cells to produce IL-8 (CXCL8). IL-8 is a potent chemokine that is responsible for the recruitment of neutrophils and macrophages to infected tissues.

Tfh Cells—CD4+ follicular helper T cells (Tfh) are a recently recognized cell type that populate the lymph node follicles and participate in antigen-specific B cell help. These cells assist with isotype switching and antibody production. The Tfh cells express the chemokine receptor CXCR5 and produce the cytokine, IL-21, both of which are required for their contribution to germinal center formation.

T regs—CD4 T cells can become T regulatory (T regs) when they are exposed to TGF-β alone. T reg cells function by suppressing T-cell responses. They are identified by expression of CD4 and CD25 molecules on their surface and the transcription factor, Foxp3. T reg cells produce TGF-β and IL-10, which can suppress immune responses.

2. CD8 effector cells—CD8 cells differentiate into effector cytotoxic cells by engagement of their TCR and recognition of class I MHC–peptide complex on the surface on an infected cell. Following recognition, the CD8 T cell proceeds to kill the infected cell. The primary method of killing is through cytotoxic granules containing perforin, the family of granzymes, and a third protein recently identified, granulysin. The CD8 T cell releases perforin that helps granzyme and granulysin enter the infected cell. Granzyme initiates apoptosis (programmed cell death) by activating cellular caspases. It should be noted that a similar process occurs with CD8 T cell recognition of tumor cells. For additional information on this topic, see Murphy et al (2017).

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مواضيع ذات صلة

Cytokines

Complement Deficiencies and Pathogen Evasion

Complement Pathways

Antibody Responses

Immunoglobulin Genes and Generation of Diversity

Immunoglobulin Classes

Immunofluorescence

Chemiluminescence

Enzyme Immunoassay

Capillary Electrophoresis

Antibody Structure and Function

B Cell Receptor for Antigen