1. T-cell activation through the antigen receptor
T-cell activation through the antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse 
Andre E. Nel, MD 
Journal of Allergy and Clinical Immunology 
Volume 109, Issue 5, Pages (May 2002)
DOI: /mai
Copyright © 2002 Mosby, Inc. Terms and Conditions

2. Fig. 1
The role of the TCR/CD3 complex and the CD4 receptor in the initiation of early protein tyrosine phosphorylation. A , On binding to the peptide/MHC complex, the earliest recognizable event is activation of the Src-kinases, Lck and Fyn. This requires removal of a C-terminal phosphate (red dot) by the tyrosine phosphatase, CD45. This allows the kinase to unfold and to phosphorylate ITAM motifs (blue rectangles in the intracellular domains of CD3δ, ϵ, γ, and ζ). Tandem ITAM phosphorylations are required for the recruitment of ZAP-70, which attaches by a pair of SH2 domains (yellow half circles) . B , Immobilized ZAP-70 is phosphorylated and activated by Lck, which interacts directly with ZAP-70. CD4 interacts with nonpolymorphic MHC domains, serving to stabilize TCR/ligand interactions and promoting further tyrosine phosphorylation. Once activated, ZAP-70 phosphorylates substrates such as LAT, SLP-76, and Vav. Lateral displacement of CD45 and other tyrosine phosphatases from the TCR/APC contact site promotes unopposed PTK activity.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
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3. Fig. 2
The kinetic segregation model of TCR triggering and formation of the immunologic synapse. The presence of large molecules (eg, CD45, CD43, and other glycoproteins) prevents close membrane contact between the T cell and APC, thereby acting to constrain engagement of the peptide-MHC complex (A) . By comparison, the TCR-CD3 complex and accessory receptors (eg, CD4 and CD28) are much smaller, which requires large molecules to migrate laterally to allow the smaller receptors to interact. This small-scale segregation of receptors leads to the formation of a specialized contact zone known as the immunologic synapse (B) . Because large-sized tyrosine phosphatases (eg, CD45) are excluded from the synapse, tyrosine kinases dominate, preparing the receptor for triggering. TCR triggering, with the assistance of co-stimulatory receptors, initiates active large-scale segregation of receptors, signaling molecules, and cytoskeletal elements, leading to the formation of SMACs (Fig 3).
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
Copyright © 2002 Mosby, Inc. Terms and Conditions

4. Fig. 3
Cross-section of the mature immunologic synapse showing the arrangement of receptors, signaling molecules, and cytoskeletal proteins in the SMACs. In the mature synapse TCR/CD3, CD28, and several signaling molecules congregate in the center of the SMACs, also known as the cSMAC. A second group of molecules, including the adhesion receptors LFA-1 and intracellular adhesion molecule 1 and the cytoskeletal protein talin form a ring around the cSMAC, to form the outer ring of the peripheral or pSMAC. The inner ring of the pSMAC includes the CD2 receptor, which interacts with LFA-3 or CD48 on the opposing APC.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
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5. Fig. 4
Examples of key adapter proteins that play a role in TCR signaling. A shows the formation of a signaling complex that regulates IP turnover and [Ca2+]i flux. The importance of modular binding domains in facilitating interactions between LAT, SLP-76, Gads, and Itk is demonstrated: SH2 ()), SH3 (υυυυ), PH (vvvv), and PR (filled circles) . B shows the use of modular domains in the formation of signaling complexes that lead to Vav and Ras activation, respectively. The former complex includes LAT/Gads/SLP-76 and PI-3 kinase, and the latter involves LAT/Grb2 and Sos.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
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6. Fig. 5
Signaling domains of the CD28 receptor (numbering according to the murine protein sequence). The 41 aa cytoplasmic tail contains 4 tyrosine residues, 2 of which (Y170 and Y188) are phosphorylated during CD28 ligation by B7 ligands. pY170 recruits PI-3 kinase, which may play an indirect role in Vav activation by allowing this protein to dock to D3-phosphorylated IP in the surface membrane. CD28 further assists in the activation of Vav by enhancing its tyrosine phosphorylation by either a TCR- or CD28-associated PTK. Vav is involved in cytoskeletal assembly through the activation of Rac-1 and also plays a role in the recruitment of PKCθ and possibly JNK activation. Notice that through its effects on the cytoskeleton, CD28 may also be responsible for the polarization of lipid rafts at the TCR synapse. The constitutive association of PTKs, such as Lck, with these rafts may lead to a generalized increase in protein tyrosine phosphorylation on TCR engagement. Two proline-rich domains (PR1 and PR2) are functionally involved in the recruitment and the activation of the Tec kinase, Itk. In addition, these PR domains are recognized by the SH3 domain of Lck and may play a role in the activation of that kinase. Although the exact role of these PTKs in CD28 signaling is unclear, they could contribute to phosphorylation of the Y170 and Y188 residues, as well as to the overall increase in PTK activity during CD28 costimulation.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
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7. Fig. 6
Components of the various MAPK families and their relationship to TCR and CD28 costimulation. The MAPKs are phosphorylated and activated by MAP2Ks, which, in turn, are activated by several MAP3Ks. A variety of transcription factors are phosphorylated and activated by these cascades, as demonstrated.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
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8. Fig. 7
Schematic to explain synergistic activation of the IL-2 promoter by Ca2+/calcineurin, Ras/MAP, and NF-κB cascades. The role of cyclosporin A and tacrolimus (FK506) in disrupting activation of the IL2 gene is demonstrated. The CD28 response element (CD28RE) is a combinatorial element that requires activation of both the NF-κB and JNK cascades. Both cascades are dependent on CD28 costimulation. The role of the negative regulatory elements CREB/CREM and NRE-A in the induction of T-cell tolerance is discussed in part 2 of this review.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
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9. Fig. 8
Schematic to explain the role of CD28, lipid rafts, and the cytoskeleton in the recruitment and activation of PKCθ and the IKK complex. This diagram shows how activation of PI-3 kinase and Vav by the CD28 receptor leads to assembly of the actin cytoskeleton. It also highlights the role of PKCθ in the activation of the IKK complex and the subsequent NF-κB activation.
Journal of Allergy and Clinical Immunology  , DOI: ( /mai )
Copyright © 2002 Mosby, Inc. Terms and Conditions