Podcast
Questions and Answers
What is the primary role of calcineurin in T-cell activation?
What is the primary role of calcineurin in T-cell activation?
- Phosphorylating NFAT to maintain its inactive state in the cytoplasm.
- Directly binding to DNA to initiate the transcription of IL-2.
- Dephosphorylating NFAT, allowing it to translocate to the nucleus. (correct)
- Activating calmodulin to increase intracellular calcium levels.
How do cyclosporine and tacrolimus suppress the immune system?
How do cyclosporine and tacrolimus suppress the immune system?
- By promoting the phosphorylation of NFAT, keeping it in an active state.
- By preventing the activation of calmodulin.
- By forming complexes that inhibit calcineurin’s phosphatase activity. (correct)
- By directly inhibiting the T-cell receptor (TCR).
In a resting T-cell, what is the state and location of NFAT?
In a resting T-cell, what is the state and location of NFAT?
- Phosphorylated and located in the nucleus.
- Phosphorylated and located in the cytoplasm. (correct)
- Dephosphorylated and located in the nucleus.
- Dephosphorylated and located in the cytoplasm.
What is the immediate consequence of calcineurin inhibition on NFAT?
What is the immediate consequence of calcineurin inhibition on NFAT?
Which event directly leads to the activation of calmodulin?
Which event directly leads to the activation of calmodulin?
What is the role of IL-2 in T-cell activation?
What is the role of IL-2 in T-cell activation?
How do the drug-immunophilin complexes affect calcineurin?
How do the drug-immunophilin complexes affect calcineurin?
What is the ultimate effect of cyclosporine or tacrolimus on IL-2 transcription?
What is the ultimate effect of cyclosporine or tacrolimus on IL-2 transcription?
If a patient's T-cells show continuous activation despite treatment with cyclosporine, which of the following could explain this?
If a patient's T-cells show continuous activation despite treatment with cyclosporine, which of the following could explain this?
Why is the dephosphorylation of NFAT by calcineurin essential for T-cell activation?
Why is the dephosphorylation of NFAT by calcineurin essential for T-cell activation?
Flashcards
Calcineurin
Calcineurin
A calcium and calmodulin-dependent phosphatase crucial for T-cell activation; it dephosphorylates NFAT, enabling IL-2 transcription.
Calcineurin Inhibitors (CNIs)
Calcineurin Inhibitors (CNIs)
They prevent T-cell activation by inhibiting calcineurin, reducing the immune response.
Inactive NFAT
Inactive NFAT
In resting T-cells, it is phosphorylated and remains inactive in the cytoplasm.
Immunophilin-Drug Complexes
Immunophilin-Drug Complexes
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Effect of Inhibiting NFAT
Effect of Inhibiting NFAT
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T-cell Activation
T-cell Activation
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Active NFAT
Active NFAT
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Study Notes
- Calcineurin is a serine/threonine phosphatase dependent on calcium (Ca²⁺) and calmodulin.
- The enzyme plays a key role in activating T-cells.
- Calcineurin dephosphorylates the nuclear factor of activated T-cells (NFAT).
- NFAT then moves to the nucleus to boost transcription of IL-2 and other cytokines.
- These cytokines are needed for T-cell proliferation.
How Calcineurin Inhibitors Work
- Calcineurin inhibitors (CNIs) like cyclosporine and tacrolimus lower immune response by stopping T-cell activation.
Normal Calcineurin Function
- NFAT is phosphorylated (inactive) and stays in the cytoplasm in resting T-cells.
- Immunophilins do not affect NFAT and are free in the cytoplasm.
- When the T-cell receptor (TCR) is stimulated, intracellular calcium (Ca²⁺) levels increase, which activates calmodulin.
- Calmodulin then activates calcineurin, a serine/threonine phosphatase.
- Calcineurin dephosphorylates NFAT, activating it and allowing it to move to the nucleus.
- NFAT then induces the transcription of IL-2 and other cytokines, which promotes T-cell proliferation.
Calcineurin Inhibitors Action
- Cyclosporine combines with cyclophilin, and tacrolimus combines with FKBP-12 (FK506-binding protein).
- The resulting drug-immunophilin complexes bind to calcineurin, thus stopping its phosphatase activity.
- The complexes prevent calcineurin from dephosphorylating NFAT by directly inhibiting calcineurin.
- Because NFAT remains phosphorylated, it is unable to move to the nucleus.
- Without NFAT in the nucleus, IL-2 transcription is blocked, which reduces T-cell activation and proliferation.
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