You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
Register for free to read this article
As a service to the community, this article is available for free. Existing users log in.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
Toning down T cell signaling to treat autoimmunity
T cells are important for fighting infectious agents, but T cells that recognize the body’s own cells are often central to the development of autoimmune disease, leading Borroto et al. to develop a compound that hampers T cell signaling without completely blocking it. Treatment with this compound prevented or treated autoimmune disease in multiple mouse models, and the compound was demonstrated to skew human T cell differentiation toward less inflammatory subsets. Treatment with the compound did not prevent T cell pathogen responses in mice, suggesting that it would not leave patients susceptible to infection.
Abstract
Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR’s CD3ε subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low–molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 (median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell–mediated autoimmune and inflammatory diseases.
- Copyright © 2016, American Association for the Advancement of Science