A nondeletional mechanism for central T-cell tolerance

To be positively selected, immature thymocytes must receive signaling throu gh their T-cell receptor (TCR), and engagement of relatively low-affinity s elf-peptides permits further T-cell maturation. However, mature T cells no longer overtly respond to such low-affinity antigens, indicating that T cel ls acquire a higher threshold for activation during thymopoiesis. We wonder ed whether partial interference in positive selection could produce T cells that respond to the selecting self-peptide. This possibility was tested by injecting procainamide-hydroxylamine (PAHA), a lupus-inducing drug, into t he thymus of adult normal mice. Three weeks after the second injection, IgG antichromatin antibodies appeared in the circulation and remained for seve ral months. The murine antichromatin antibodies reacted with the (H2A-H2B)- DNA subnucleosome complex, the predominant specificity in patients with pro cainamide-induced lupus. In thymus organ and reaggregate cultures, PAHA had no effect on negative selection of T cells with high affinity for a co-pre sent antigen, but acted on CD4(+)CD8(+) immature T cells as they underwent positive selection. TCR transgenic T cells specific to cytochrome c peptide 88-104 acquired the capacity to respond to the low-affinity analogue at po sition 99 (lys --> ala) if PAHA was present during their development. PAHA also blocked the capacity of a T-cell line to become anergic after anti-CD3 treatment, suggesting that PAHA prevents the production of negative regula tors that accumulate in response to partial signaling through the TCR. Thes e results are consistent with the view that T cells acquire self-tolerance during positive selection, and disruption of this process can result in aut oreactive T cells and systemic autoimmunity.