TCR: TOLERANCE AND MHC RESTRICTION

What is the function of positive selection in T cell development?

To ensure developing T cells (DP thymocytes) recognize self-MHC molecules. Only those that bind moderately to self-MHC + peptide complexes on cortical epithelial cells (CEC) receive survival signals and mature further.

Where does positive selection occur and which cells mediate it?

Occurs in the thymic cortex and is mediated by cortical epithelial cells (CEC) presenting self-peptides on MHC molecules.

What does MHC restriction mean in T cell development?

T cells are “restricted” to recognizing antigens only when presented by self-MHC molecules, established during positive selection.

What happens if a DP T cell does not interact with any MHC during development?

It dies by neglect due to lack of survival signals—failure of positive selection.

What is the function of negative selection in T cell development?

To eliminate T cells that bind too strongly to self-peptides presented on self-MHC, thus preventing autoimmunity.

What cytokine receptor do positively selected thymocytes express to move to the medulla?

They upregulate CCR7, guiding them to the medulla for negative selection.

What is central tolerance?

Tolerance mechanisms that occur in the thymus, including positive and negative selection, to prevent autoreactive T cells from entering the periphery.

What is peripheral tolerance in the immune system?

A form of immune tolerance that occurs outside the thymus to prevent activation of self-reactive T cells that escaped central tolerance.

What are the three major mechanisms of peripheral tolerance?

Anergy, Regulatory T cells(Tregs), Activation-induced cell death (AICD)

What is T cell anergy?

A state in which a T cell becomes functionally unresponsive after encountering an antigen without co-stimulatory signals (e.g., no CD28-B7 interaction).

What causes a T cell to enter an anergic state?

Antigen recognition by the TCR without co-stimulation, such as in the absence of CD28 engagement with B7 on an APC.

How do regulatory T cells (Tregs) promote peripheral tolerance?

By expressing inhibitory signals like CTLA-4, which competes with CD28 and removes co-stimulatory molecules (CD80/86) from APCs, reducing T cell activation.

What is CTLA-4 and what is its role in peripheral tolerance?

CTLA-4 is an inhibitory receptor on Tregs that binds B7 with higher affinity than CD28, thereby suppressing T cell activation.

What is activation-induced cell death (AICD)?

A mechanism where repeated or chronic stimulation of a T cell leads to apoptosis, often through Fas-FasL signaling, eliminating autoreactive cells.

How does Fas-FasL interaction contribute to peripheral tolerance?

Fas (on T cells) binding to FasL triggers apoptotic death of T cells, helping terminate overactive or autoreactive immune responses.