Abstracts (complete list) - Wissenschaft Online

Dietmar Zehn, Michael J. Bevan
Lack of peripheral control of low avidity self reactive T cells
Autoimmune diseases develop despite the presence of numerous safeguards to
eliminate or control T cells directed against self-antigens. This raises the question how
disease-causing T cells escape elimination or inactivation. We have studied the
repertoire of T cells directed against a pancreatic antigen that is also ectopically
expressed in the thymus. T cells responding strongly to this antigen are efficiently
eliminated. In contrast, central and peripheral tolerance routinely fail to eliminate cells
that are weakly reactive with this organ specific self-antigen. These low avidity T cell
cause autoimmunity upon activation via molecular mimicry. While in the periphery,
these low avidity T cell continuously encounter tissue derived cognate self-antigen
crosspresented by lymph node dendritic cells. We have analyzed how this chronic
exposure impacts the low avidity T cells. Our data indicate that the low avidity cells can
be detected throughout life and retain their disease causing potential as the mice age.
Moreover, the ability to recruit low avidity T cells into autoimmune responses does not
rely on the supply of recent thymic emigrants nor does the presence or absence of the
cognate self-antigen in the periphery alter the reactivity of these low avidity T cells. In
the model we study, low avidity self-reactive T cells are long lived populations that are
not changed by peripheral antigen recognition. Thus, we conclude that cells like these
are a normal part of the T-cell repertoire in healthy individuals. The constitutive
presence of such cells requires mechanisms that prevent their activation. Unexpectedly,
the selective elimination of Foxp3+ T cells did not enhance autoimmunity, but rather
interfered with the ability of low avidity T cells to induce disease.