T Cell Signaling Pathways

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

Describe how the amplification of an initial signal occurs in signaling pathways, providing at least two distinct mechanisms with specific examples from the text.

Amplification occurs through: 1. Activation of multiple downstream kinases by a single activated kinase (e.g., Raf activating many kinases). 2. Production of numerous second messenger molecules by activated enzymes (e.g., PLC-γ generating DAG and IP3). Also, the release of preformed second messenger $Ca^{2+}$ can activate many further molecules (e.g.calmodulin)

Explain the structural composition of the T cell receptor (TCR) complex and delineate the roles of its variable and invariant components in antigen recognition and signal transduction.

The TCR complex consists of variable antigen-recognition proteins (TCR) and invariant signaling proteins (CD3 ε, δ, γ, ε chains and the 2 ζ chains). The TCR binds to the antigen, while the CD3 and ζ chains contain ITAMs that initiate signaling upon antigen binding.

Define ITAMs and outline their function in the context of antigen receptor signaling, specifically detailing the molecular events that occur following the binding of a cognate peptide/MHC to the TCR.

ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) are cytoplasmic recognition motifs containing two tyrosine residues. Upon cognate peptide/MHC binding to the TCR. ITAMs get phosphorylated, which then recruit signaling proteins with tandem SH2 domains.

Contrast the roles of ZAP-70 and Syk kinases in antigen receptor signaling, specifying which receptor complex each is associated with and how they contribute to downstream signaling events.

ZAP-70 is recruited to phosphorylated ITAMs of the T-cell receptor, while Syk is recruited to phosphorylated ITAMs of the B-cell receptor. Both kinases, once bound, phosphorylate downstream targets to propagate the signal. Signup and view all the answers

Describe the dual role of the co-receptors CD4 and CD8 in enhancing T cell receptor signaling, detailing how they contribute to both the stabilization of the TCR-MHC complex and the phosphorylation of ITAMs.

CD4 and CD8 stabilize the TCR-MHC complex and enhance phosphorylation of ITAMs. Lck, bound to the cytosolic part of CD4, phosphorylates ITAMs once CD4 associates with the TCR complex. Signup and view all the answers

How does ZAP-70's phosphorylation of LAT and SLP/76 result in enhanced integrin activation and adhesiveness?

ZAP-70 phosphorylates LAT and SLP/76 triggering downstream signaling modules. One of these modules leads to inside-out signaling, which alters the conformation of integrins, increasing their affinity for ligands and promoting cell adhesion. Signup and view all the answers

Explain the role of Akt in promoting cell survival and how it connects to metabolic activity within T cells after TCR signaling.

Akt inhibits cell death pathways, promoting T cell survival. Simultaneously, Akt activates mTOR, a key regulator of cellular metabolism, increasing metabolic activity to support cell growth, proliferation, and effector functions. Signup and view all the answers

Describe the mechanism by which the rapamycin-FKBP complex inhibits cell growth and proliferation. Why is this useful in the context of transplant rejection?

The rapamycin-FKBP complex blocks the activation of mTOR by Raptor. This inhibition interferes with cell cycle progression and proliferation. This is useful in transplant rejection as it suppresses the proliferation of T cells that would otherwise attack the transplanted organ. Signup and view all the answers

How do transcription factors activated by ZAP-70 contribute to the adaptive immune response?

Transcription factors activated by ZAP-70 bind to DNA and regulate the expression of genes encoding cytokines, chemokines, and other effector molecules. These molecules shape the adaptive immune response by directing immune cell differentiation, recruitment, and function. Signup and view all the answers

Explain how the drug Rapamycin (sirolimus) works on a molecular level.

Rapamycin binds to FKBP forming a complex. This complex binds to mTOR, specifically blocking mTOR's interaction with Raptor. By preventing the mTOR-Raptor interaction, rapamycin inhibits mTOR's kinase activity, which is essential for cell growth and proliferation. Signup and view all the answers

How does TCR signaling activation of Akt relate to increased metabolic activity?

Akt activates mTOR, a central regulator of cellular metabolism. mTOR increases the rate of protein synthesis, lipid synthesis, and glucose uptake, thereby boosting overall metabolic activity to support T cell growth, proliferation, and effector functions. Signup and view all the answers

Describe how cytoskeletal rearrangement, initiated by ZAP-70, helps T cells perform their immune functions.

Cytoskeletal rearrangement allows T cells to change shape, move efficiently, and form stable contacts with antigen-presenting cells. This is essential for T cell migration to sites of infection, antigen recognition, and delivery of effector functions such as cytokine secretion and target cell killing. Signup and view all the answers

How does FcgRIII on NK cells mediate antibody-dependent cell cytotoxicity (ADCC), and what role do ITAM-containing chains play in this process?

FcgRIII, upon binding to antibodies on target cells, activates intracellular signaling pathways through its associated ITAM-containing chains. ITAM phosphorylation leads to the recruitment and activation of kinases, triggering NK cell cytotoxicity and the release of cytotoxic granules to kill the target cell. Signup and view all the answers

Describe the specific roles of LAT and SLP-76 as scaffold proteins in T cell signaling, and explain how their phosphorylation by ZAP-70 contributes to the activation of downstream signaling modules.

LAT and SLP-76 are scaffold proteins that, upon phosphorylation by ZAP-70, recruit and organize other signaling molecules. This organization facilitates the activation of downstream pathways involved in transcription factor activation, metabolic activity, cytoskeletal rearrangement, and integrin activation, all critical for T cell activation and function. Signup and view all the answers

Explain how the activation of transcription factors, increased metabolic activity, cytoskeletal rearrangement, and enhanced integrin activation collectively contribute to T cell activation, proliferation, and differentiation following ZAP-70 phosphorylation of LAT and SLP-76.

Activation of transcription factors leads to the expression of genes necessary for T cell function and proliferation. Increased metabolic activity supports the energy demands of proliferation and effector function. Cytoskeletal rearrangement enables cell movement and interaction with other cells. Enhanced integrin activation promotes stable interactions with antigen-presenting cells and target cells, all contributing to T cell activation, proliferation, and differentiation into effector cells. Signup and view all the answers

What are the implications of cytoskeletal rearrangement in the context of T cell activation, and how does this process facilitate the formation of the immunological synapse?

Cytoskeletal rearrangement allows T cells to reorganize their surface receptors and signaling molecules at the site of contact with antigen-presenting cells, facilitating the formation of the immunological synapse. This synapse concentrates signaling molecules and promotes efficient T cell activation by enhancing receptor-ligand interactions. Signup and view all the answers

Rituximab is an anti-CD20 antibody that mediates its anti-cancer effects through ADCC. Outline the molecular events, initiated by Rituximab binding to CD20, that lead to the killing of cancer cells by NK cells.

Rituximab binds to the CD20 protein expressed on cancer cells. The Fc region of Rituximab is then recognized by FcgRIII receptors on NK cells, triggering ADCC. This interaction activates the NK cells, leading to the release of cytotoxic granules containing perforin and granzymes, which induce apoptosis in the CD20-expressing cancer cells. Signup and view all the answers

Explain why the phosphorylation of LAT and SLP-76 is crucial for the downstream activation of PLC-γ in antigen receptor signaling.

Phosphorylation of LAT and SLP-76 creates binding sites for signaling molecules, including PLC-γ. This recruitment and subsequent phosphorylation of PLC-γ are essential for its activation and downstream signaling. Signup and view all the answers

Describe the distinct roles of diacylglycerol (DAG) and inositol-triphosphate (IP3) in signal transduction following PLC-γ activation, and how each contributes to the activation of specific transcription factors.

DAG remains in the membrane to recruit PKC-θ and RAS-GRP which leads to the activation of AP-1 and NFκB. IP3 induces $Ca^{2+}$ release from the ER, leading to activation of calcineurin, dephosphorylation of NFAT, and its subsequent translocation to the nucleus. Signup and view all the answers

Explain the mechanism by which calcineurin activation leads to NFAT translocation into the nucleus, and why this step is essential for T cell activation.

Calcineurin, a phosphatase, is activated by $Ca^{2+}$-calmodulin. It dephosphorylates NFAT, exposing a nuclear localization signal that allows NFAT to translocate into the nucleus, where it activates the transcription of genes like IL-2, crucial for T cell activation. Signup and view all the answers

How does IL-2 signaling contribute to T cell activation, and why is blocking this signaling pathway a viable target for immunosuppression?

IL-2 promotes T cell proliferation and differentiation in an autocrine manner. Blocking IL-2 signaling inhibits T cell activation, reducing immune responses, which is useful in preventing transplant rejection or treating autoimmune diseases. Signup and view all the answers

Describe the mechanism by which Cyclosporin A inhibits T cell activation at the molecular level, including the specific molecules involved and the ultimate effect on gene expression.

Cyclosporin A forms a complex with immunophilin, which inhibits calcineurin. This prevents the dephosphorylation of NFAT, thus blocking its translocation to the nucleus and subsequent transcription of IL-2, ultimately suppressing T cell activation. Signup and view all the answers

If a patient is prescribed Basiliximab post-transplant, how does this antibody's mechanism of action differ from that of Cyclosporin A in preventing T-cell activation and subsequent organ rejection?

Basiliximab, an anti-IL-2Ra antibody, directly blocks the IL-2 receptor on T cells, preventing IL-2 from binding and initiating its signaling cascade, thus inhibiting T-cell activation and proliferation. Cyclosporin A, however, inhibits calcineurin, which is upstream of IL-2 production, thereby preventing IL-2 transcription. Signup and view all the answers

Explain how the combined action of NFAT, AP-1, and NF-kB transcription factors results in the expression of interleukin-2 (IL-2).

NFAT, AP-1, and NF-kB bind cooperatively to the IL-2 promoter region. This collaborative binding enhances the transcriptional activity at the IL-2 gene locus, leading to increased IL-2 mRNA synthesis and, consequently, IL-2 protein production. Signup and view all the answers

A researcher introduces a non-hydrolyzable analog of IP3 into T cells. What immediate effect would you expect to observe regarding intracellular calcium levels and subsequent NFAT activation? Explain your reasoning.

The non-hydrolyzable IP3 analog would continuously bind to IP3 receptors on the ER, causing a sustained release of calcium ions into the cytoplasm. This would lead to prolonged activation of calmodulin and calcineurin, resulting in enhanced dephosphorylation and nuclear translocation of NFAT. However, because the IP3 analog cannot be broken down, you'd expect eventual desensitization or toxicity due to calcium overload. Signup and view all the answers

The recruitment and activation of PLC-g results in the generation of IP4 and DAG, which are crucial second messengers, initiating the activation of transcription factors.

False (B) Signup and view all the answers

In T cells, the phosphorylation of CD27 enhances signaling, leading to the activation of PI3K and PLCg, subsequently activating the transcription factors NFAT, NFkB, and AP1.

False (B) Signup and view all the answers

The ultimate outcome of T cell activation includes altered metabolic activity and survival, decreased adhesiveness, and inhibition of cytoskeletal rearrangements.

False (B) Signup and view all the answers

IL-2 functions as an autocrine T cell survival factor, and its signaling is therapeutically targeted by Cyclosporin A and Basiliximab, which are used in the treatment of bacterial infections.

False (B) Signup and view all the answers

CTLA-4, primarily expressed on antigen-presenting cells, enhances T cell activation by binding to B7 molecules with lower affinity than CD28.

False (B) Signup and view all the answers

CTLA-4 genetic mutations leading to loss of function are typically associated with immunosuppression due to its inhibitory role in T cell activation.

False (B) Signup and view all the answers

Checkpoint inhibitors, such as Ipilimumab, function by downregulating anti-tumor T cell responses, making them effective in treating autoimmune diseases but contraindicated in cancer therapy.

False (B) Signup and view all the answers

PD-L2, and not PD-1, is another co-inhibitory receptor on T cells targeted by antibodies in cancer therapy.

False (B) Signup and view all the answers

Inhibitory receptors enhance the immune response by recruiting protein or lipid phosphatases, which dephosphorylate key signaling molecules.

False (B) Signup and view all the answers

ITAMs (immunoreceptor tyrosine-based activation motifs) recruit activating phosphatases, which initiate downstream signaling cascades.

False (B) Signup and view all the answers

ITIMs (immunoreceptor tyrosine-based inhibition motifs) recruit inhibitory kinases such as SHP and SHIP to dampen immune cell activation.

False (B) Signup and view all the answers

NK cells exclusively express activating receptors to identify and kill infected or damaged cells.

False (B) Signup and view all the answers

Activating receptors on NK cells recognize cell-surface proteins suppressed in target cells by stress or damage, leading to inhibition of cell killing.

False (B) Signup and view all the answers

Inhibitory receptors on NK cells recognize surface molecules absent at high levels, such as MHC class III molecules, thereby preventing unwarranted cell death.

False (B) Signup and view all the answers

Signaling pathways commonly involve the inactivation of Ser/Thr kinases and tyrosine kinases.

False (B) Signup and view all the answers

Signaling in immune cells exclusively leads to proliferation and differentiation, but not changes in cell shape or migration.

False (B) Signup and view all the answers

Phosphorylation of LAT and SLP-76 initiates the recruitment and activation of phospholipase C-g (PLC-$\gamma$).

True (A) Signup and view all the answers

PLC-$\gamma$ activation leads to the activation of transcription factors NFAT, NF$\kappa$B, and AP1, which are independently sufficient for interleukin-2 expression.

False (B) Signup and view all the answers

Diacylglycerol (DAG) recruits PKC-$ heta$ and RAS-GRP, subsequently leading to the activation of AP-1 and NF$\kappa$B.

True (A) Signup and view all the answers

Inositol-triphosphate (IP3) directly activates NFAT by binding to it and altering its conformation.

False (B) Signup and view all the answers

Calmodulin inhibits calcineurin activity by preventing its interaction with NFAT.

False (B) Signup and view all the answers

NFAT translocation to the nucleus is inhibited by its phosphorylation status, which is reversed by the action of calcineurin.

True (A) Signup and view all the answers

Blocking IL-2 transcription or autocrine IL-2 signaling enhances T cell activation by preventing negative feedback loops.

False (B) Signup and view all the answers

Cyclosporin A directly binds to and inhibits the catalytic activity of calcineurin.

False (B) Signup and view all the answers

Basiliximab induces immunosuppression by directly inhibiting the phosphatase activity of calcineurin.

False (B) Signup and view all the answers

Flashcards

ITAM-linked receptors

Receptors that pair with ITAM-containing chains to deliver activating signals.

ADCC

An antibody-dependent cellular cytotoxicity; when NK cells recognize antibodies bound to target cells, inducing cell death.

ZAP-70

A protein tyrosine kinase that phosphorylates LAT and SLP-76, initiating downstream signaling modules in T cell activation.

LAT & SLP-76

Proteins phosphorylated by ZAP-70, involved in initiating downstream signaling modules (activation of transcription factors, increased metabolic activity, cytoskeletal rearrangement, enhanced integrin activation and adhesiveness)