Re: What is the difference between MHC restriction and self-tolerance?

Hi Jane-

Thanks for posting a question to the MadSci Network. Wow - an immunology course online. Good for you. :)

You asked what the difference between MHC restriction and self-tolerance is. This is one of the central concepts of immunology. As you know, most T lymphocytes (T cells) need to see cognate peptide + MHC in order to be activated. There are also other types of T cells that can recognize lipids and/or lipopeptides in the context of CD1 or other antigen- presenting molecules, but for the purposes of this question, we will not discuss these T cells. The fact that T cells need to see antigen (peptide) in the context of a particular MHC is called "MHC restriction." This is the result of the fact that the T cell receptor (TCR) makes contact with both the MHC molecule itself, as well as the peptide that is bound into the MHC groove. Here is one of the original crystal structure papers of a TCR complex interacting with MHC by Ian Wilson's group http://www.s ciencemag.org/cgi/content/full/274/5285/209. In figure 9, you can see the "footprint" of the TCR on the MHC molecule and the bound peptide.

In an unmanipulated animal, T cells are restricted to self MHC. This restriction is imposed in the thymus, where T cells must undergo "positive selection" to not die from neglect. T cells with a TCR that cannot recognize self MHC (bound to self peptide) in the thymus do not receive a survival signal and die. This removes useless T cells from the repertoire, ones that cannot recognize MHC + antigen. Positive selection, however, poses a potential problem: the T cells in the thymus are selected on MHC+self peptide. This means of ensuring functionality also holds the seeds of autoimmunity. Therefore a second selection step must take place: negative selection.

Negative selection is achieved as the thymocytes move deeper into the thymic cortex and to the corticomedullary junction. In this case, if T cells bind too tightly/well to self peptide + MHC, they will receive a strong stimulatory signal and die by apoptosis. This process removes most self-reactive T cells. After the newly formed T cells are released into the circulation and the periphery, they are also somewhat sensitive to deletion, allowing the generation of peripheral tolerance to antigens not expressed in the thymus.

I hope this helps-
ILD
MadScientist

Good immunology texts:
Immunobiology by Janeway/Travers
Immunology by Kuby
Fundamental Immunology by Paul
Cellular and Molecular Immunology by Abbas, Lichtman and Pober

All of these should be available in a medical library. Good luck with your course!