Lecture 24 Flashcards
What is negative regulation in the immune system?
Negative regulation controls the immune response using receptors, mechanisms, and specific cell types (like Tregs) to prevent excessive or prolonged activation.
Which cell type is important in negative regulation of the immune system?
Treg (regulatory T) cells.
How long does the immune response typically last before contracting?
10–14 days.
What happens to most lymphocytes after the antigen (Ag) is removed?
Most lymphocytes are no longer needed and undergo apoptosis (programmed cell death).
How do Treg cells help regulate immune responses after the antigen is removed?
Treg cells release inhibitory cytokines to suppress immune responses.
What happens to most newly generated B and T cells at the end of the primary immune response?
They are lost through apoptosis.
Why are most effector cells no longer needed after the antigen (Ag) is cleared?
The immune response is no longer needed once the threat is removed.
How do most effector cells die after the antigen is cleared?
By apoptosis (programmed cell death).
How does the intrinsic pathway of apoptosis work?
- Called “death by neglect”
- IL2Rα and other cytokine receptors have transient expression
- Lack of signaling through these receptors → absence of survival signal → apoptosis
How does the extrinsic pathway of apoptosis work?
- Triggered by Fas-FasL interaction
- Involves cytotoxic T lymphocytes (CTLs)
- Leads to apoptosis
What happens to most effector T cells after the immune response ends?
At least 90% die, leaving behind antigen-specific memory T cells.
How do memory T cells respond to a subsequent exposure to the same antigen?
They respond with heightened reactivity, leading to a faster and more robust secondary response.
What is the function of CTLA-4 in T cell regulation?
CTLA-4 downregulates T cell activation, proliferation, and survival by binding to B7.1/B7.2 with higher affinity than CD28, shutting down signaling pathways and preventing excessive immune responses.
When is CTLA-4 induced and when does it peak after T cell activation?
CTLA-4 is induced within 24 hours after activation and peaks 2–3 days post-stimulation.
How does CTLA-4 compete with CD28 for B7 binding?
CTLA-4 binds to B7.1/B7.2 with higher affinity than CD28, sequestering B7 and preventing CD28 from binding.
Where is CTLA-4 found before and after activation?
CTLA-4 is found intracellularly and is expressed on the cell membrane after phosphorylation.
How many B7 molecules can one CTLA-4 molecule bind?
One CTLA-4 molecule can bind two B7 molecules.
How can CTLA-4 strip B7 molecules from antigen-presenting cells (APCs)?
In some cases, CTLA-4 can physically remove B7 molecules from APC surfaces, further reducing CD28 stimulation.
What is the difference between CTLA-4 and CD28 expression in naïve vs. activated T cells?
- CD28 is expressed by naïve T cells.
- CTLA-4 is only expressed on the surface after activation of naïve T cells (after receiving signals 1 and 2).
How does CTLA-4 affect T cell sensitivity and IL-2 production?
CTLA-4 makes activated T cells less sensitive to stimulation by APCs and reduces IL-2 production.
What is the overall effect of CTLA-4 on the immune system?
CTLA-4 prevents overgrowth of lymphocytes and limits excessive immune responses.
When is PD-1 expressed on T cells?
PD-1 is expressed on activated T cells.
What are the ligands for PD-1 and where are they found?
PDL-1 → Expressed by many cells
PDL-2 → Expressed on APCs during inflammation
What is the function of PD-1 signaling in T cells?
PD-1 signaling downregulates T cell activation, proliferation, and function.
What does PD-1 act as a marker for in chronic diseases?
PD-1 is a marker of T cell exhaustion in chronic diseases.
How is PD-1 targeted in cancer therapy?
Blocking PD-1, PDL-1, or CTLA-4 is used in some cancer treatments to restore T cell activity.
What cytokines (Signal 3) are required to induce iTregs (induced Tregs)?
IL-2 and TGF-β.
What are the effector cytokines secreted by iTregs?
IL-10 and TGF-β (anti-inflammatory cytokines).
What is the master transcriptional regulator for iTregs?
FoxP3.
What is the function of iTregs in immune regulation?
Suppress immune responses and maintain immune tolerance to self-antigens (prevent autoimmunity).
Where do induced Tregs (iTregs) arise?
In the periphery (lymph nodes) from CD4⁺ T cells.
What transcription factor is involved in iTreg signaling?
STAT5 (activated by IL-2 and TGF-β).
Where do natural Tregs (nTregs) originate?
In the thymus.
What are natural Tregs (nTregs) selected for?
High affinity for self-peptides (to dampen immune responses to them).
What markers are expressed on natural Tregs?
TCR
CD4
IL2Rα
CTLA-4
FoxP3
Why are natural Tregs unable to provide IL-2?
They rely on other cells to supply IL-2.
How do Treg cells deplete the local area of stimulating cytokines?
By expressing IL2Rα (CD25) to sequester IL-2.
How does CTLA-4 inhibit APC activity?
- Sequesters B7 → reduces co-stimulatory molecule expression
- Reduces pro-inflammatory cytokine secretion
- Decreases T cell differentiation and activation
What immunosuppressive cytokines do Tregs produce?
IL-10 and TGF-β.
How can Tregs directly kill T cells?
Through granzymes and metabolic disruption.
How does IL-10 affect other T cells?
- Inhibits production of TH1 and TH17 cytokines
How does TGF-β affect T cells?
- Inhibits T cell proliferation
- Inhibits the development and function of TH1 and TH2 cells
What type of antigens do T cells and Tregs recognize?
- T cells → Peptides from dangerous non-self antigens
- nTregs → Self-peptides (from thymus)
- iTregs → Self or commensal peptides (from periphery)
Where do nTregs and iTregs arise?
nTregs → Thymus
iTregs → Periphery
How are most autoreactive T cells handled during development?
Most are deleted in the thymus during development.
What happens if a Treg recognizes its p:MHC on an APC presenting self-peptides?
Tregs secrete cytokines to inhibit neighboring T cells recognizing other self-peptides:MHC from becoming activated.
