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Chapter 14 : T-Cell Maturation and Activation

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Abstract:

The structure of the thymus provides an environment where immature thymocytes can interact with a variety of cells, including thymic epithelial cells and dendritic cells, to acquire their final functional properties—expression of a major histocompatibility complex (MHC)-restricted T-cell receptor (TCR), presence of either CD4 or CD8 in the plasma membrane, and ability to interact with antigen-presenting cells (APCs) or nucleated target cells to respond to foreign antigens. Negative selection that occurs in the thymus forms the basis for central tolerance or the process whereby the large pool of emerging mature lymphocytes is screened for self-reactivity and eliminated if improperly reactive. As with positive selection, controversy particularly exists over which cells in the thymus mediate negative selection and whether it takes place in the cortex or the medulla of the thymus. Peripheral tolerance refers to all of the tolerogenic mechanisms acting on mature lymphocytes that have already proceeded through all of the B- and T-cell maturation stages, have left the primary lymphoid organs, and have entered the periphery. The major transcription factor is NF-κB, generated from a cytoplasmic precursor held in check by binding to its inhibitor, IκB. While obviously not physiologically relevant to T-cell activation, laboratory methods represent important tools for studying the complexity of T-cell responses.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14

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Immune Systems
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Amino Acids
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Major Histocompatibility Complex
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Immune Cells
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MHC Class II
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Figures

Image of Figure 14.1
Figure 14.1

Early events in T-cell maturation in the thymus. Precursor thymocytes bearing surface markers (Thy-1, a mouse-specific marker, and c-kit and CD44) enter the thymus, facilitated by CD44 binding to cell surface receptors expressing hyaluronate. ckit engages its receptor, stem cell factor (SCF), which leads to the production of IL-7R on the cell surface. When IL-7 is made, the IL-7R leads to changes in the chromatin structure and the accessibility of the DNA encoding the γ chain of the TCR to initiate TCR recombination events.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.2
Figure 14.2

Identification of T-cell development in the thymus and correlation with the migration of the cells. The precursor T cells are initially found in the outer cortex and are identified as TN cells because they lack production of CD3, CD4, and CD8. The cells then produce CD3 but still do not express CD4 or CD8 and are called DN. The cells pass through more mature TN stages, then into the DP state, indicating that they express both CD4 and CD8, and finally in the SP state they migrate out of the thymus.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.3
Figure 14.3

Changes in T cells as they go through development stages in the thymus. The thymic T-cell maturational stage correlates with changes in cell surface markers. The clonogenic lymphoid precursor can give rise to T cells, B cells, or NK cells. The first identifiable T-cell maturation stage, TN1, is characterized by the presence of the CD44 marker (CD44) and lack of CD25 marker (CD25). As the cells progress through various TN stages, there are changes associated with the cell surface markers and the generation of TCR. Correlated with these developmental steps are changes in gene expression, notably transcription factors. Most T cells will produce an αβ TCR. Just before production of the TCR α chain at the DP stage, either CD4 or CD8 genes are transcribed, leading to an initial single-positive (iSP) stage. Following full production of the TCR along with CD4 and CD8 the cells become SP, producing only CD4 or CD8 in association with a specific MHC-restricted TCR.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.4
Figure 14.4

Commitment to αβ or γδ lineage and formation of the pre-TCR. Changes in levels of the IL-7R α chain (CD127) are associated with development of either αβ or γδ T cells. Both development lines appear to involve a CD44 CD25 stage, followed by a CD44 CD25 stage associated with the pre-T-cell stage for αβ T cells. The ultimate fate of the T cell depends on signaling via the type of TCR produced. Formation of the pre-TCR complex on a developing αβ T cell. Expression of the TCR β chain requires the presence of an invariant chain termed pre-T alpha (pre-Tα). This receptor is associated with the production of the CD3. Pre-TCR formation signals the cells to expand and differentiate further into mature αβ T cells, a process designated β selection.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.5
Figure 14.5

T-cell development and pre-TCR signaling. Once the pre-TCR complex is formed, signals are sent to the cell via a variety of pathways to promote various activities critical for T-cell development. Much of the signaling occurs through the protein kinases Lck and Fyn. Survival signals involve activation of the p53 transcription factor and inhibition of the Fas-activated death domain (FADD). Proliferation and differentiation signals involve the Ras pathway as well as PLCγ1 and PKC factors. Activation of PKC is also involved in allelic exclusion. ERK is a transcription factor that is needed for survival, proliferation, and differentiation.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.6
Figure 14.6

Models of lineage commitment to CD4 or CD8. In transgenic mice, increases in the relative levels of p56 increase the ratio of CD4 cells to CD8 cells up to a point. Relative expression over threefold of normal returns the ratio of CD4 to CD8 cells to normal. Reprinted from S. J. Sohn et al., 2209–2217, 2001, with permission. Development of an SP cell depends on the strength of the signal from the cytoplasmic domain of the CD4 or CD8 coreceptor. A CD8 extracellular domain binding to MHC class I engineered to express a CD4 cytoplasmic tail (cyt.) will produce a strong Lck signal and develop into a CD4 T cell in spite of binding to the MHC class I molecule. Similarly, a cell engineered to express a CD4 extracellular domain that binds to MHC class II fused with a CD8 cytoplasmic tail will become a CD8 T cell.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.7
Figure 14.7

Schematic diagram showing the thymic cell types that are important in the induction of central tolerance. In the outer cortex of the thymus much of the positive selection takes place. Here the maturing thymocyte interacts with thymic epithelial cells. Those that receive sufficient survival signals due to appropriate interactions with self MHC-peptide can move on to the next stage, negative selection. Those that do not receive sufficient survival signals die by apoptosis. In the medullary area, the thymocytes interact with interdigitating dendritic cells, which arise extrathymically. Here much of the negative selection takes place, where thymocytes that interact too strongly with self MHCself peptide receive a strong signal due to a high-affinity interaction from the TCR engagement and die by apoptosis.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.8
Figure 14.8

T cells are positively selected by the MHC phenotype of the thymus. An F heterozygous mouse ( ) is thymectomized and lethally irradiated to destroy all of its hematopoietic capacity. This results in an mouse with no thymus or bone marrow. This mouse then receives a thymus transplant from a mouse with only one of the parental haplotypes, , and a bone marrow transplant from an isogenic sibling. This leaves a mouse with an endogenous overall background, an thymus and bone marrow. After recovery, the mouse is immunized with lymphocytic choriomeningitis virus (LCMV) to generate cytolytic CD8 T cells. After an immune response is made, the T cells in the spleen are tested for their ability to kill LCMV-infected or cells. The immune T cells efficiently kill the virus infecting targets, but not targets, indicating the T cells were positively selected in the thymus to recognize targets. As a control, H-2 cells infected with a different virus were not killed, demonstrating the immunologic specificity of the experiment.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.9
Figure 14.9

Signaling for positive selection of T cells. TCRs that cannot engage self MHC-self peptide die via apoptosis due to neglect because they fail to receive survival signals. Those T cells that produce a TCR able to bind to self MHC-self peptides will receive signals through the TCR complex that affect cell survival. If too strong a binding occurs and a high signal intensity is generated through the TCR, then the cell will not survive. If the binding of TCR to MHC-peptide is of modest affinity, then a pattern of survival signals is generated.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.10
Figure 14.10

Peptide influences on the strength of T-cell activation. Alternate forms of peptides that bind to the same MHC and engage the same TCR have an effect on cellular activation delivered through the TCR. Agonist peptides bind to the TCR strongly and give a strong activation or survival signal. Partial agonist peptides weakly activate T cells, whereas antagonist peptides prevent TCR-mediated signaling and lead to no activation.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.11
Figure 14.11

Integrated model of T-cell survival during positive selection. When a TCR that has a moderate association constant for self peptide- MHC and a high dissociation constant is produced, a series of signals are delivered, resulting in a sustained level of the transcription factor ERK, which is needed for T-cell survival. When there is a high association and low dissociation between the TCR and self peptide- MHC, the T-cell signaling is intense but short-lived and the cell does not receive survival signals to get it through the stage of positive selection. If there is no ability of the TCR to bind self peptide-MHC, the cell dies via apoptosis.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.12
Figure 14.12

Negative selection eliminates self-reactive T cells. T cells that survive positive selection may still be capable of binding to self-peptide- MHC complexes inappropriately. During negative selection, self antigens presented by IDCs or thymic epithelial cells (TEC) that bind to TCR with low affinity give rise to survival signals. The resultant cell can now recognize foreign peptide complexed to self MHC, but not self peptide complexed to self MHC. A high-affinity interaction leads to either more intense or qualitatively different signaling, leading to apoptosis and elimination of self-reactive T cells.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.13
Figure 14.13

The role of thymic epithelial cells in negative selection of CD4 T cells. In a thymic culture system, intrathymic dendritic cells and other cells arising in the bone marrow were destroyed by incubation in deoxyguanosine, leaving only thymic cells of nonhematopoietic origin. If this thymus is then seeded with fresh thymocytes, mature CD4 thymocytes are subjected to negative selection, even in the absence of thymic interdigitating dendritic cells. Survival of autoreactive CD8 T cells indicates a role for bone marrow-derived cells in negative selection of these T cells.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.14
Figure 14.14

Potential basis for alloreactivity. In all cases, a T cell (green) specific for peptide X presented by MHC allele A interacts with different APCs. Self APC (pink) could present peptide X, leading to T-cell activation, or peptide Y, which will not activate the T cell. In some instances when a nonself APC (yellow) presents a peptide (Z) (which can be a self peptide for the nonself APC), the T cell recognizes this complex and is activated. Alloreactivity is actually quite common, with up to 10% of T cells able to respond to a large population of cells expressing nonself MHC but presenting their own cells' peptide antigens.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.15
Figure 14.15

Different mechanisms leading to nonresponsiveness of T cells. In the thymus, clonal deletion via negative selection eliminates potentially self-reactive T cells. Also in the thymus, clonal anergy can put potentially self-reactive T cells into a state of anergy, rendering them nonharmful when they encounter self antigens. In the periphery, self-reactive T cells can be eliminated by clonal deletion if they encounter self antigen but do not receive activation signals but instead signals to undergo apoptosis. Self-reactive T cells that encounter self antigen in the absence of costimulation can enter an anergic state and remain unresponsive to antigenic stimulus. Regulatory or suppressor cells can keep potentially self-reactive T cells in check. Immune privilege sites represent places in the body where resident cells constitutively express Fas ligand (CD95L), and when Fas (CD95)-bearing T cells enter the tissue, they undergo apoptosis subsequent to engaging the FasL.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.16
Figure 14.16

T-cell tolerance can be induced by “incomplete” signaling through the TCR. On the left, the T cell receives an activation signal consisting of antigen-MHC binding to TCR/CD3/CD4 as well as costimulatory signals such as the interaction of CD80 or CD86 on the APC with T-cell costimulatory receptor CD28. Engagement of CD28 on the T cell helps mobilize the TCR into membrane rafts (green area of membrane) containing key signaling molecules. Further events downstream of these initial interactions lead ultimately to entry of multiple transcription factors into the nucleus (light gray area) and cellular activation. In contrast, on the right, the T cell receives an incomplete signal consisting of TCR/CD3/CD4 engagement, but no CD28 engagement (tolerogenic signal). The resulting signal cascade fails to activate the T cell because an insufficient level or number of transcription factors enter the nucleus. This incomplete signal instead induces a state of anergy.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.17
Figure 14.17

Function of regulatory T cells. At the core of this mechanism of T-cell regulation are CD4 CD25 T cells that can mediate a variety of functions by secreting soluble factors or possibly via direct cell contact. A blockade of IL-2 production will remove a critical factor T cells need for growth and differentiation. IL-10 and transforming growth factor β (TGF-β) are well-known factors that inhibit lymphocyte function and responses. Regulating T-cell homeostasis and controlling clonal deletion also have been proposed as mechanisms of action of regulatory T cells. Experimental evidence for the existence and function of regulatory T cells. Isolated T cells from the spleen of a normal BALB/c mouse can be separated by flow cytometry on the basis of expression of surface markers. The separated cells can then be transferred in various combinations to an athymic mouse lacking an endogenous immune system. The mice are then monitored for the development of autoimmune disease. Athymic mice that get unfractionated or a whole population of T cells develop no significant autoimmune disease whereas mice that get those T cells lacking CD25 (CD25) go on to develop autoimmune disease. If CD4 but CD25 cells are transferred, then autoimmune disease also frequently develops. In contrast, CD8 cells that are CD25 do not promote autoimmune disease, indicating a regulatory role for these T cells. If the population of autoimmune-promoting CD25 cells are mixed with the autoimmune-inhibiting CD25 cells, then the latter cells can prevent the development of autoimmune disease.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.18
Figure 14.18

Evidence for the existence of regulatory T cells in an experimental model of multiple sclerosis (experimental autoimmune encephalomyelitis). When injected with myelin basic protein (MBP), MBPspecific CD4 and CD8 T cells become activated and expand. The CD4 cells provide help to the CD8 cells that mediate the pathologic disease process. These MBP-reactive T cells express TRBV13-2, then attack nerve cells coated with MBP and destroy them, leading to autoimmune encephalomyelitis. If mice are immunized with CD8 CTL expressing TRBV13-2 or soluble TRBV13-2 molecules, they will develop CD8 CTL that recognize peptide fragments of TRBV13-2 presented by MHC antigens of TRBV13-2 T cells. Mature T cells can express both MHC class I and class II. The CTL that can now recognize the TRBV13-2 cells usually express TRBV31 and are cytolytic to the TRBV13-2 cells.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.19
Figure 14.19

Regulation of T-cell and complement activation at sites of immune privilege. In the testes, stromal cells constitutively express CD95L (Fas ligand). Binding of CD95L to CD95 (Fas) on T cells triggers apoptosis of the latter, thus preventing immune responses within the testes. In the placenta, privilege has been shown to be maintained by two mechanisms. First, IDO secreted by trophoblast cells consumes all available tryptophan (Trp), thus killing immune cells by amino acid starvation. Second, the placenta controls complement activation by constitutive expression of the complement regulatory protein Crry, which binds C4b and prevents the formation of the C4b2a “C3 convertase.”

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.20
Figure 14.20

The immunologic synapse. . In one model, binding of TCR to MHC-peptide facilitates movement of this complex into lipid rafts. These molecules are then concentrated in the middle of the synapse. A ring of accessory molecules is formed, involving ICAM-1 and LFA-1 among others to exclude unnecessary factors. In another model, most of the TCR engages Lck at the periphery of the synapse before formation of the mature synapse, and TCR-based signaling is mostly over by the time the mature synapse forms. The TCR may be internalized from the synapse by endocytosis for either further intracellular signaling or attenuation of signaling due to removal of the TCR from the cell surface.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.21
Figure 14.21

Initial events in T-cell activation. Following ligation of TCR and CD4 to MHC-peptide, the activity of the CD45 protein tyrosine phosphatase dephosphorylates the terminal phosphate (orange) on p59 and p56. The activated Fyn and Lck are themselves phosphorylated (green circles) by protein tyrosine kinases, and they then phosphorylate tyrosine molecules located in the cytoplasmic ITAMs (red).

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.22
Figure 14.22

Full T-cell activation. ZAP-70, a Src family kinase, binds to phosphorylated ITAMs of the ζ chain homodimer via SH2 domains. ZAP-70 is phosphorylated by Lck and Fyn, and the activated ZAP- 70 phosphorylates the linker of activation in T cells (LAT) and SLP-76. LAT is concentrated within the lipid rafts and can be phosphorylated to provide docking sites for enzymatic signaling molecules that bind via SH2 domains. The complex of activated ZAP-70, LAT, and SLP-76 is then able to activate a number of other targets, prominent among which is PLCγ1, which is activated upon phosphorylation. The substrate for PLCγ1 is PIP, which results in formation of IP and DAG. Production of IP and DAG results in additional effects that are part of T-cell activation. A major consequence is the activation of second messengers such as calcineurin and PKC. These then act on inactivated forms of transcription factors held in the cytoplasm. Both dephosphorylation (i.e., of NF-AT) and phosphorylation (i.e., of IκB) events produce activated transcription factors that then translocate from the cytoplasm to the nucleus. The transcription factors bind to regulatory regions in chromosomal DNA to activate transcription of genes that characterize an activated T cell.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.23
Figure 14.23

G proteins involved in T-cell activation. G proteins are potent activators and controllers of cellular growth. Activated ZAP-70 phosphorylates (green circles) p21 and CDC42/ (yellow ovals) after recruitment of these molecules to the cell membrane when the costimulatory molecule CD28 is engaged by CD80 or CD86. The activation state of G proteins is determined by whether they are bound to GDP or GTP. An active G protein is bound to GTP, and becomes inactive when dephosphorylated to produce GDP. Guanine-nucleotide exchange factors (GEF) act on GDP-bound small G proteins to exchange GDP for GTP and reproduce the active form of the G protein. The activated small G proteins initiate other signaling cascades, particularly those that comprise the MAPK cascade.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Image of Figure 14.24
Figure 14.24

Final stages of T-cell activation. Entry of transcription factors into the nucleus with subsequent transcription of genes needed for activation and proliferation mediate the final stages of T-cell activation. NF-κB is derived from an inactive precursor in the cytoplasm. Phosphorylation of the inhibitor of κB (IκB) by IKK releases the active form for nuclear translocation. Calcineurin dephosphorylates NF-AT for its nuclear translocation. Phosphorylated Ras and Rac activate members of the MAPK family—JNK and the MAPK kinase kinase (MAPKKK). Phosphorylated JNK translocates into the nucleus where it acts on a transcription factor, Jun, allowing it to pair with another factor, Fos. This combination forms the AP-1 transcription factor. MAPKKK acts on another kinase, MAPKK, which acts on another kinase, MAPK, that translocates into the nucleus and activates additional transcription factors.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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Figure 14.25

Mode of binding of superantigens to MHC-TCR. Normally, the TCR recognizes the MHC-peptide complex on an APC . Superantigens bind to the variable region of the TCR β chain outside of the antigen-recognition area as well as to the MHC class II on the APC. This mimics cognate recognition by the TCR of peptide- MHC, leading to T-cell activation.

Citation: Pier G, Ceri H, Mody C, Preston M. 2004. T-Cell Maturation and Activation, p 315-342. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch14
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