More MS news articles for Mar 2002

T Cell Response in Experimantal Autoimmune Encephalomyelitis (EAE): Role of Self and Cross-Reactive Antigens in Shaping, Tuning, and Regulating the Autopathogenic T Cell Repertoire

Annu Rev Immunol 2002;20:101-123
Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115

T cells that can respond to self-antigens are present in the peripheral immune repertoire of all healthy individuals.

Recently we have found that unmanipulated SJL mice that are highly susceptible to EAE also maintain a very high frequency of T cells responding to an encephalitogenic epitope of a myelin antigen proteolipid protein (PLP) 139-151 in the peripheral repertoire.

This is not due to lack of expression of myelin antigens in the thymus resulting in escape of PLP 139-151 reactive cells from central tolerance, but is due to expression of a splice variant of PLP named DM20, which lacks the residues 116-150.

In spite of this high frequency, the PLP 139-151 reactive cells remain undifferentiated in the periphery and do not induce spontaneous EAE.

In contrast, SJL TCR transgenic mice expressing a receptor derived from a pathogenic T cell clone do develop spontaneous disease.

This may be because in normal mice, autoreactive cells are kept in check by an alternate PLP 139-151 reactive nonpathogenic repertoire, which maintains a balance that keeps them healthy.

If this is the case, selective activation of one repertoire or the other may alter susceptibility to autoimmune disease.

Since T cells are generally cross-reactive, besides responding to nonself-antigens, they also maintain significant responses to self-antigens. Based on the PLP 139-151 system, we propose a model in which activation with foreign antigens can result in the generation of pathogenic memory T cells that mediate autoimmunity.

We also outline circumstances under which activation of self-reactive T cells with foreign antigens can generate selective tolerance and thus generate protective/regulatory memory against self while still maintaining significant responses against foreign antigens.

This provides a mechanism by which the fidelity and specificity of the immune system against foreign antigens is improved without increasing the potential for developing an autoimmune disease.