Homegrown Cure for Autoimmune Disease
Approach Mobilizes Natural Killers to Wipe Out Turncoat T cells
Researchers have discovered a way to help the immune system help itself to destroy the disease-causing T cells responsible for autoimmune diseases such as type 1 diabetes and multiple sclerosis.
The work, from HMS professor of pathology Harvey Cantor and colleagues at the Dana–Farber Cancer Institute, reveals a natural mechanism of immunosuppression that involves the direct killing of self-reactive T cells by another immune actor, the natural killer (NK) cell. The study brings to light an unexpected regulatory role for these deadly attackers, better known for their ability to purge tumor cells or virus- infected tissues.
Normally, T cells repel the NK cell assault by expressing the major histocompatibility protein Qa-1. This immune molecule shuts down NK cells by binding to the inhibitory cell surface protein NKG2A, the researchers report in the May issue of Immunity.
Disrupting the Qa-1/NKG2A coupling to promote the NK-dependent killing of T cells could lead to safer and more effective treatments for autoimmune disorders. Blocking the interaction with a monoclonal antibody to Qa-1 allowed the NK cells to deliver a deathblow to overactive T cells, the researchers demonstrate. The antibody regimen dramatically reduced the severity of autoimmune disease in a mouse model of multiple sclerosis.
“This work represents a proof of principle, that you can mobilize the body’s own cellular mechanism for controlling the immune system to dispose of unwanted self-reactive cells,” Cantor said.
Though all the work was done in mice, analogous proteins exist in humans, and so the investigators hope that the results will translate into clinical investigations before too long. The approach could potentially offer treatments for autoimmune diseases like multiple sclerosis, some forms of arthritis, and type 1 diabetes, and to reduce the rejection of transplanted tissues.
Teaming T Cells
Linrong Lu, the first author of the new report, followed up these results by showing that even if the recipient mice were vaccinated with foreign antigen or treated with an autoantigen, the Qa-1–minus T cells did not expand. The mice never developed the long-lasting memory T cells that recognize antigen quickly the second time around. The Qa-1–lacking T cells also failed to induce experimental allergic encephalitis (EAE) in mice, a model of the human autoimmune disease multiple sclerosis.
The researchers immediately suspected the work of NK cells, said Lu. They had known for some time that NK cells could kill T cells when the two were mixed together in a test tube. T cells loaded with Qa-1, however, were resistant to killing because Qa-1 turns off the cytotoxic activity of NK cells. So Lu hypothesized that Qa-1 might function in vivo to regulate the life of T cells by shielding them from NK cells. T cells that lacked Qa-1 would be vulnerable to attack.
To test their hypothesis, the researchers transplanted Qa-1-knockout T cells into recipient mice that lack NK cells. In those mice, the transplanted T cells grew just fine, and the mice developed memory T cells as usual.
The protective role of Qa-1 fits with the current understanding of normal NK function. NK cells are programmed to kill any cells that do not display sufficient levels of major histocompatibility proteins, cell surface markers that help the immune system distinguish self from non-self. The Qa-1 class of MHC protein protects the T cell by interacting with the protein on the surface of NK cells, NKG2A, which turns off the killing machinery. Lu’s results suggest that if Qa-1 is missing, NK cells are no longer inhibited and kill the T cells.
To prove that the Qa-1/NKG2A interaction is critical for T cell survival, Lu generated knock-in mice in which the endogenous Qa-1 gene was replaced with a mutant Qa-1 that abolished NKG2A binding but maintained other functions of the protein. Just like the knockouts, T cells from the Qa-1–mutant mice were resistant to killing by NK cells after transplantation and protected mice from EAE. “With a knockout, a lot of things might change, but the knock-in we made has a single amino acid change which affects the Qa-1/NKG2A interaction specifically,” Lu said. “This result is the key to show that’s the exact interaction responsible.”
If activated T cells need Qa-1 to survive, Lu wondered whether specifically disrupting the Qa-1/NKG2A partnership could entice NK cells to eliminate autoreactive T cells. To test this idea, the researchers asked if a monoclonal antibody to Qa-1 that blocked NKG2A binding could prevent disease in the EAE model of multiple sclerosis. They found that treating mice with anti–Qa-1 after the disease-induction phase greatly reduced the intensity of EAE symptoms, due to elimination of the T cells by NK cells.
Reducing Collateral Damage
“The advantage of our approach,” Cantor explained, “is that Qa-1 and its human homolog HLA-E are MHC molecules, not activating receptors. Engaging them does not result in the same kind of aberrant signaling that might result from engagement of a receptor molecule. An antibody that attaches to HLA-E and blocks its interaction with inhibitory receptors on NK cells is not likely to otherwise disturb the cell it binds to. So the approach is probably less prone to side effects.”
To find that out as quickly as possible, Cantor hopes to develop mice that express the human HLA-E gene. These mice would allow testing of a panel of monoclonal antibodies for their ability to turn down immune responses. “If successful, these preclinical studies could lead directly to the use of this approach in people,” he said.