How The Immune System Avoids Attacking Itself

Immune cells called T lymphocytes recognize invaders in the body, such as viruses, bacteria, tumor cells, or allergens. Normally, T cells are activated by a complex series of signals that end with the destruction of the foreign substance. However, some T cells are not activated, in fact they are inactivated by a process called anergy or tolerance. This process helps prevent immune cells from attacking themselves and other normal cells and proteins.

"How T lymphocytes become activated or inactivated has been one of the major questions in the field of immunology," says senior author Koretzky. "Our discovery shows that DAGs are critical for T-cell activation so these cells can respond to foreign invaders. However, when DAGs are chemically modified by enzymes called diacylglycerol kinases, T cells become tolerant or unresponsive to foreign substances and to self."

The discovery was made by studying mice that had been engineered to lack diacylglycerol kinases (DGKs). Although T cells from these knock-out mice were normal in most respects the induction of tolerance was impaired. When DAGs could not be chemically altered because the DGKs were absent, the T cells were hyperreactive to foreign antigens and could not be made tolerant to host cells.

Hyperreactivity was shown when purified T cells from DGK knockout mice were stimulated by antigen in a culture dish. The failure of the T cells to become tolerant was demonstrated in experiments where mice were treated with a toxin from staphylococcal bacteria that should have induced unresponsiveness. Instead, the T cells produced about five times more of an immunity factor than did cells from normal mice.

The hyperreactive state, if controlled, might be beneficial to the body under some circumstances; for example, some T cells might be made more effective at eliminating tumors. The research team is continuing to study DGK knock-out mice to see if they are more resistant to tumors. If the hyper-reactive T cells in these mice recognize the tumor cell as a foreign invader, then the tumor might be eliminated or reduced. Conversely, if the tolerant state could be induced in a controlled manner, it might benefit individuals with autoimmune disease or help prevent rejection of transplants.

This work was funded by a grant from the National Institutes of Health and the support of the Abramson Family Cancer Research Institute. Co-authors, in addition to Koretzky, are Benjamin A. Olenchock and Martha Jordan from Penn, as well as Rishu Guo, Jeffery H. Carpenter, and Xiao-Ping Zhong from Duke University Medical Center and Matthew K. Topham from the University of Utah.