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Searching for T Cell Peptide Antigens

Research Summary

John Kappler's lab studies the nature of foreign and self-antigens recognized by the T cell arm of the immune system.

Within the body's immune system, T cells are extremely important in the recognition and destruction of foreign substances that enter the body. The protein molecule on the surface of the T cell responsible for this recognition is the αβ T cell receptor (αβTCR). Each T cell has a slightly different form of this receptor, so each T cell recognizes a different foreign intruder. Since there are many millions of T cells, our immune system is capable of dealing with virtually any virus, bacterium, fungus, and parasite—even those that do not yet exist in nature. Each of these invaders contains proteins called antigens that are unique to the organism and not present in our bodies. These antigens are the recognition targets for T cells.

T cells detect their target antigen in an unusual way. The protein antigen must first be partially degraded to small proteins, called peptides. Some of these peptides become associated on the surface of our cells with one of a specialized set of molecules encoded by genes in the major histocompatibility gene complex (MHC). The T cell receptor actually recognizes the combination of the peptide and MHC molecules, so that, in a way, the recognition of a foreign antigen always involves the simultaneous recognition of a self-molecule. This complicated recognition scheme focuses T cells where they will do the most good. For example, when a virus infects a cell, that cell's MHC molecules display viral antigen peptides on the cell surface. T cells whose function it is to destroy the virally infected cells are not distracted by the free virus that may be found elsewhere in the body but zero in on the infected cell by recognizing the combination of viral peptide and MHC molecule.

This type of T cell recognition does not always work in our favor. Although during T cell development the immune system takes pains to eliminate from its repertoire those T cells that might recognize MHC-bound peptides derived from our own proteins, this process is not foolproof. For example, in autoimmune diseases, such as arthritis, diabetes, and multiple sclerosis, some T cells mistakenly recognize MHC-bound peptides derived from self-proteins and attack the tissues of the host. Also, in some cases of allergy, T cells recognize self-peptides that have been modified by the allergen. For example, the widespread sensitivity to nickel jewelry is thought to involve the binding of the nickel metal ion to an MHC-bound self-peptide, changing its shape and fooling the immune system into thinking that the MHC molecule contains peptide derived from a foreign protein. A similar hypothesis has been offered to explain the devastating T cell–mediated inflammatory disease berylliosis, which occurs in some individuals chronically exposed to the metal beryllium.

To study how T cells recognize these inappropriate, self-protein–derived peptide antigens, we have collaborated with a series of laboratories to assemble a collection of T cell clones from mice or humans that are involved in the autoimmune diseases rheumatoid arthritis and diabetes or in allergic responses to the metals nickel or beryllium. In each case, although we know the MHC molecule involved, we do not know the self-protein that contributes the peptide portion of the T cell target. We have used our knowledge of how peptides bind to MHC molecules to prepare libraries of many millions of different random peptide-MHC combinations. We have also developed high-throughput methods to find the particular combinations of peptide and MHC in these libraries that are recognized by a particular T cell. Our goals are to identify the self-protein source of the peptides recognized by these T cells and to use x-ray crystallography to understand the atomic details of the recognition. Our hope is that this information will be useful in the design of vaccines, therapeutics, and diagnostics.

This work is also supported in part by grants from the National Institutes of Health.

As of June 08, 2007

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