Researchers showed that a protein known as H2-DM can keep immune system T cells from erroneously assaulting the body's own tissues. Distinguishing between foreign and native is one of the immune system's most important tasks; failure to make this distinction can lead the immune system to attack the body, causing autoimmune conditions like diabetes, lupus, arthritis and multiple sclerosis.
"This protein may be one of the components that goes awry when the immune system's normal inflammatory processes malfunction, leading some T cells to attack the body," says Scott Lovitch, an M.D./Ph.D. student at Washington University and member of the research team. The work will be published this week in the journal Immunity.
Lovitch works in the laboratories of the study's principal investigator, Emil R. Unanue, M.D., the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology. Unanue's research team studies a group of T cells known as type B T cells.
"During development, as the body begins building its arsenal of T cells to attack various types of invaders, any T cells that attack the body's own tissues are supposed to be deleted," Lovitch explains. "However, our laboratory determined that some of these self-reactive T cells don't get eradicated. These cells are known as type B T cells."
T cells normally go on the attack when other cells known as antigen-presenting cells supply evidence of a foreign invasion. This evidence takes the form of protein bits on the surface of antigen-presenting cells. Based on its inspection of these protein bits, a T cell will either remain inactive or start multiplying in preparation for an attack.
The protein bits are displayed in molecules collectively known as the major histocompatibility complex (MHC). Unanue's lab previously found evidence that type B T cell attacks on the body's own tissues were linked to slight changes in ways the MHC displays bits of protein.
A piece of one of the body's own proteins displayed in the MHC might not normally provoke a type B T cell, for example. But that same protein part displayed in a slightly altered form of the MHC changes what the T cell "sees," possibly leading the T cell to attack.
Lovitch developed a test tube approach for inserting proteins into specific compartments of antigen-presenting cells. He found that when the proteins were given to a compartment in the cell known as an endosome, the proteins were displayed by the MHC in a fashion that could provoke type B T cells. However, when they were given to another compartment known as a lysosome, the MHC-protein display failed to provoke the type B T cells.
Scientists then tried the experiment in cells in which the gene for the H2-DM protein had been removed. H2-DM is common in lysosomes but rare in endosomes, and other scientists have shown that high-acidity environments like the lysosome increase H2-DM's activity levels.
In this experiment, they found that antigen presenting cells could provoke a reaction in type B T cells regardless of which compartment received the protein.
"These results suggest that H2-DM appears to be playing an editing role in the lysosome, blocking the pathway that leads to an MHC-protein complex that can cause a response from type B T cells," Lovitch says.
To further investigate the potential links between H2-DM, type B T cells, and autoimmune disease, Lovitch and others in Unanue's lab have produced a genetically altered mouse that only has type B T cells. They plan to study these mice to determine whether normal inflammation can provoke an autoimmune reaction in the T cells, leading to conditions similar to diabetes.
Pu Z, Lovitch SB, Bikoff EK, Unanue ER. T Cells Distinguish MHC-Peptide Complexes Formed in Separate Vesicles Edited by H2-DM. Immunity, April 2004
Funding from the National Institutes of Health.
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