Action of Critical Component in Immune System Activation Described for First Time by UB Scientists

BUFFALO, N.Y. -- Immunologists from the University at Buffalo are the first to describe a human immune system component known to be essential to controlling the activation of T-cells, the first line of defense against foreign antigens.

Results of the research appear in the September issue of Nature Immunology.

UB scientists report than an adapter protein known as CARMA1 acts as a switch mediating activation of several transcription factors essential to controlling multiple genes for inflammation, anti-apoptosis (programmed cell death) and T-cell proliferation.

This finding identifies CARMA1 as a potential target for drugs that could be designed to enhance the immune system in immune-compromised patients, dampen it to prevent tissue and organ rejection, and control the proliferation of T-cells to treat leukemia, said Xin Lin, assistant professor of microbiology in the UB School of Medicine and Biomedical Sciences and the senior author on the study.

Co-first-authors are Donghai Wang, a graduate student, and Yun You, M.D., a postdoctoral fellow, both in the UB Department of Microbiology.

Lin and colleagues were particularly interested pinpointing activation of a group of transcription factors known as the NF-KB family, which is responsible for a wide range of immune system responses, including the production of interleukin-2 (IL-2), which modulates the production of helper T-cells.

Wang, You and Lin cloned a CARMA1-deficient T-cell line, and found that a deficiency of this protein selectively impaired the activation of NF-KB, which resulted in defective IL-2 production. Restoring CARMA1 to the cell line also restored the signaling system.

Finding a signal that recognizes a specific antigen and triggers the proper immune response is essential for successful drug intervention, Lin noted.

"T-cells play the most critical role in recognizing foreign antigens. Each subset of T-cells will recognize a specific antigen, and must be regulated to respond at the right time and in the right number. Overreaction causes autoimmune disease and uncontrolled growth of white blood cells, which results in leukemia. Destroying T-cells causes immune deficiency. The idea in a properly functioning immune system is to elicit a very specific response."

While events surrounding the initial stimulation of T-cell receptors by antigens have been studied intensively, signaling components further down the cascade of reactions regulating the immune system's response have been largely unknown, Lin said.

"We provide genetic evidence to show that this protein is an important link in the signaling pathway of T-cells," said Lin. "If we can understand T-cell receptor actions, we will be able to shut down the pathway or design drugs to act on the pathway."

Also contributing to the study were Linda M. McAllister-Lucas and Gabriel Nuñez of the University of Michigan Medical School, and Lin Wang, Peter S. DiStefano and John Bertin of Millennium Pharmaceuticals, Inc.

The research was funded by UB.