Peripheral T cell Tolerance - Clonal Deletion and Anergy (FL-Immuno/78)

Summary

The lecture discusses peripheral T-cell tolerance, explaining how autoreactive T cells, which escape central tolerance, are managed to prevent autoimmune responses. Key mechanisms include clonal deletion, where autoreactive T cells are eliminated through apoptosis, and anergy, which inactivates T cells without complete activation. The role of dendritic cells is highlighted, as they present self-antigens in the absence of danger signals, leading to T cell tolerance. Additional mechanisms like immune deviation and regulatory T cells further control immune responses. The importance of maintaining immune homeostasis is emphasized, setting the stage for a subsequent discussion on B-cell tolerance.

Takeaways

• 😀 Central T-cell tolerance eliminates auto-reactive T cells in early developmental stages within central lymphoid organs, but it is not foolproof.
• 😀 Peripheral tolerance prevents self-reactive T cells from attacking tissues, with mechanisms like clonal deletion, anergy, immune deviation, and regulatory T cells.
• 😀 Danger signals such as cytokines, chemokines, and microbial products are produced during infections or injuries, activating dendritic cells and triggering immune responses.
• 😀 Immature dendritic cells mature in response to cytokines, and once activated, they present antigens to naive T cells in lymphoid tissues.
• 😀 Complete activation of naive T cells requires three signals: recognition of antigen-MHC complex, co-stimulation (via B7-CD28 interaction), and cytokine release from T cells.
• 😀 Autoreactive T cells recognize self-antigens, which are not associated with danger signals, making them different from responses to infections or injuries.
• 😀 In the absence of danger signals, dendritic cells do not express co-stimulatory molecules, leading to the deletion or inactivation of autoreactive T cells.
• 😀 Peripheral clonal deletion occurs when autoreactive T cells are eliminated by apoptosis, while anergy occurs when these cells are inactivated without differentiation into effector cells.
• 😀 Immune deviation shifts harmful immune responses to less harmful ones, while immune privilege refers to body sites less exposed to immune responses (e.g., CNS, eyes, testes).
• 😀 Immunosuppressive molecules like IL-10 and TGF-beta inhibit immune responses by suppressing macrophages, inflammatory cytokines, and antigen-presenting cells.
• 😀 Regulatory T cells control activated T cell responses, block proliferation, and secrete immunosuppressive cytokines, contributing to peripheral tolerance.

Q & A

What is the main purpose of peripheral tolerance?

The main purpose of peripheral tolerance is to ensure that autoreactive T cells that escaped central tolerance do not attack self tissues, preventing autoimmune responses.

What are the key mechanisms of peripheral tolerance?

The key mechanisms of peripheral tolerance include peripheral clonal deletion, anergy, immune deviation, immune privilege, immunosuppressive molecules, and regulatory T cells (Tregs).

What is peripheral clonal deletion, and how does it work?

Peripheral clonal deletion is a process where autoreactive T cells are eliminated through programmed cell death (apoptosis) when they bind to self-antigens presented by dendritic cells without co-stimulatory signals.

What role do dendritic cells play in peripheral tolerance?

Dendritic cells process and present self-antigens to T cells. In the absence of danger signals, they do not express co-stimulatory molecules, leading to T cell apoptosis or anergy.

What happens when a T cell binds to a self-antigen without co-stimulation?

When a T cell binds to a self-antigen without co-stimulation, it undergoes apoptosis or becomes anergic, preventing it from differentiating into effector cells and avoiding an immune response.

How does immune deviation contribute to peripheral tolerance?

Immune deviation refers to the alteration of a potentially harmful immune response to a less harmful one, reducing the risk of autoimmune damage and maintaining tolerance.

What is the significance of immune privilege in peripheral tolerance?

Immune privilege refers to anatomical sites like the brain, eyes, and testes, which are less susceptible to immune responses, thereby reducing the risk of self-reactive immune activity in these areas.

How do immunosuppressive molecules contribute to peripheral tolerance?

Immunosuppressive molecules like IL-10 and TGF-beta inhibit macrophage activation, reduce inflammatory cytokine secretion, downregulate T cell signaling, and block antigen-presenting cell function, helping control the immune response.

What is the function of regulatory T cells (Tregs) in peripheral tolerance?

Regulatory T cells (Tregs) control the responses of activated T cells by blocking their proliferation and secreting immunosuppressive cytokines, maintaining immune tolerance.

What happens when dendritic cells present self-antigens without danger signals?

When dendritic cells present self-antigens without danger signals, they do not express co-stimulatory molecules, leading to the absence of second signals required for T cell activation. This results in the apoptosis or anergy of autoreactive T cells.