CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose

There are two major mechanisms reported to prevent the autoreactivity of is let-specific CD8(+) T cells: ignorance and tolerance. When ignorance is ope rative, naive autoreactive CD8(+) T cells ignore islet antigens and recircu late without causing damage, unless activated by an external stimulus. In t he case of tolerance, CD8(+) T cells are deleted. Which factor(s) contribut es to each particular outcome was previously unknown. Here, we demonstrate that the concentration of self antigen determines which mechanism operates. When ovalbumin (OVA) was expressed at a relatively low concentration in th e pancreatic islets of transgenic mice, there was no detectable cross-prese ntation, and the CD8(+) T cell compartment remained ignorant of OVA. In mic e expressing higher doses of OVA, cross-presentation was detectable and led to peripheral deletion of OVA-specific CD8(+) T cells. When cross-presenta tion was prevented by reconstituting the bone marrow compartment with cells incapable of presenting OVA, deletional tolerance was converted to ignoran ce. Thus, the immune system uses two strategies to avoid CD8(+) T cell-medi ated autoimmunity: for high dose antigens, it deletes autoreactive T cells, whereas for lower dose antigens, it relies on ignorance.