May lead to more effective, precisely targeted therapies for cancers and infections
The immune system's T cells have the unique responsibilities of being both jury and executioner. They examine other cells for signs of disease, including cancers or infections, and, if such evidence is found, rid them from the body. Precisely how T cells shift so swiftly from one role to another, however, has been a mystery.
In a new study, investigators at Dana-Farber Cancer Institute, Harvard Medical School, and the Massachusetts Institute of Technology used an array of techniques -- including "optical tweezers" that exploit laser light to press molecules against surface structures found on T cells -- to find out what operates the switch. Their answer: sheer mechanical force. Hence, the T cell receptor is a mechanosensor.
When a T cell's "receptors" lock onto their targeted structures called antigens on the surface of a diseased cell, parts of the receptors bend in a way that signals the T cell to change from disease-scanning to disease-fighting mode, the researchers report. (Antigens are made of peptides bound to histocompatibility proteins, or pMHCs.) They also found that after T cell receptors (TCRs) and antigens meet, an additional force generated during scanning triggers the T cell's response to disease.
Their findings will be published in the Nov. 6 issue of the Journal of Biological Chemistry and currently are available on the journal's Web site.
"The study fills a major gap in our understanding of the molecules that make up the TCR - the role they play in recognizing abnormal antigens and in subsequently activating a T cell to attack diseased cells," says senior author Ellis L. Reinherz, MD, of Dana-Farber and Harvard Medical School. "Our findings explain how TCRs can detect 'a needle in a haystack,' enabling T cells to identify infected or cancerous cells that may look very similar to normal cells, and destroy the diseased cells for the good of the body. Distinguishing between cells that belong in the body from those that don't is the key function of T cells, a discriminative task mediated by their TCRs."
Understanding the details of T cell activation opens the way to development of better immune-based therapies against viral infections and cancers, the authors state. "Vaccines have shown a great deal of promise as cancer treatments, but they need to be made more efficient," says Reinherz. "This fundamental discovery offers important insights that may make it possible to target such vaccines precisely, destroying cancer cells without the harsh side effects of more traditional therapies."
Reinherz says that a broader range of tumor antigens can be selected as potential targets because of the intrinsic sensitivity of the TCR triggering mechanism revealed by this study. Likewise, the discovery offers promise for the development of T cell-based vaccines for infectious disease prevention, currently an area almost exclusively restricted to antibody-based approaches. Antibodies target regions of viruses that vary substantially in many cases, requiring alterations of vaccines, as in the annual flu vaccines. This is not the case for T cell-based therapies, since they can target antigens that don't vary among diverse strains of the same type of virus.
Disease inspectors
T cells are white blood cells that patrol the bloodstream and body's organs for signs of disease, a process termed immune surveillance. When they encounter another cell, they "frisk" it to determine if it is normal or infected, cancerous, or foreign to the body. This inspection takes the form of the T cell brushing against the surface of the other cell. The T cell's surface bristles with receptors -- intricate webs of proteins designed to snag specific antigens, much as a lock accepts only certain keys. Each T cell displays a distinct TCR capable of binding to a specific antigen. The millions of T cells within the bloodstream protect people from a wide variety of invading germs or cells altered by cancerous changes.
TCRs are built of eight individual molecules. Investigators have sought to uncover the basic mechanics of the coupling between TCR and antigen by exploring the role of these eight molecules in recognizing foreign antigens and activating T cells' disease-fighting abilities.
First, immunologists identified monoclonal antibodies (mAbs) that target a portion of the TCR - known as CD3 subunits - involved in T cell activation. They determined which anti-CD3 mAbs activate T cells and which others are non-stimulatory. Using recombinant molecular biology, they generated pMHCs specific for, or irrelevant to, a particular TCR.
Next, structural biologists led by Harvard Medical School's Gerhard Wagner, PhD, used Nuclear Magnetic Resonance techniques to determine the shape of the TCR and the arrangement of its component molecules. Biomechanics scientists led by Matthew Lang, PhD, of MIT then devised a set of experiments involving mAbs and pMHC molecules.