Page 613 - Veterinary Immunology, 10th Edition

FIG. 20.4 How the thymus induces central T cell tolerance by
VetBooks.ir yet can still respond to foreign antigenic peptides in association with
negative selection. Surviving T cells are unreactive to autoantigens

MHC molecules as a result of positive selection.

The negative selection process is assisted by the presence of many
different self-antigens in the thymus. Normally, each tissue
possesses its own tissue-specific antigens. Thus “skin antigens” are

usually restricted to the skin, whereas “liver antigens” are restricted
to the liver, and so forth. However, the epithelial cells in the thymic
medulla show uniquely “promiscuous” gene expression. Thymic

epithelial cells use a transcription factor called the autoimmune
regulator (AIRE) that promotes the expression of thousands of non-
thymic protein antigens in the thymic medullary epithelium.
Examples include insulin, thyroglobulin, and myelin basic protein.
In this way, the thymic epithelial cells ensure that self-reactive T

cells encounter most normal tissue antigens and are eliminated if
they respond too strongly. In addition, some normal tissue antigens
may be taken up by macrophages and carried to the thymus. Self-

reactive T cells that respond to these antigens are also eliminated.
However, this raises another question: What about self-antigens
that are not expressed in, or do not enter, the thymus? Antigens
from the eye, testis, or brain are not processed in this way, and as a
result central tolerance to these antigens does not develop.

These selection processes together ensure that cells that can bind
self-antigens are positively selected and those that bind these
antigens with very low or very high affinity are subsequently

deleted. As a result, the moderate-affinity clones survive and are
available to recognize foreign antigens. An additional factor that
probably determines thymocyte survival is the dose of antigen
presented to the cells. If the amount of a specific antigen is high (as
one might anticipate for a self-antigen), multiple TCRs will be

occupied on each thymocyte and trigger apoptosis. In contrast, if
the amount is low, this will occupy only a few TCRs, and the weak
signal may result in positive selection and thymocyte proliferation.

Receptor Editing

When the antigen receptors of a developing T cell bind to self-
antigens, another strategy that prevents autoimmunity is receptor

613