David Parker, PhD, Professor, Department of Molecular Microbiology & Immunology, and his team in the Parker Lab recently published a paper in the Journal of Immunology that has been included in the F1000 index, a list of high profile scientific publications.
The paper, titled, "Cyclosporine-resistant, Rab27a-independent mobilization of intracellular preformed CD40 ligand mediates antigen-specific T cell help in vitro," addresses how helper T cells deliver specific signals to activate B cells and dendritic cells in the immune response.
T cells belong to a group of white blood cells known as lymphocytes that play a central role in immunity to infection. They recognize and react to foreign antigens on the surface of other cells. Killer T cells attack and kill virus-infected cells by releasing cytotoxic granules—a process that happens in a matter of minutes. Another kind of T cell, called a helper cell, has the ability to cause rare antigen-specific B lymphocytes to divide and produce multitudes of antibody secreting cells by delivering to the B cells a cytokine called CD40 ligand (CD40L). CD40L and other cytokines are typically newly made following antigen recognition, a process that takes several hours
Thanks to recent advances in imaging, it's now possible to measure the duration of antigen-specific interactions between helper T cells and B cells in living animals. "Surprisingly, it was found that those interactions are short, lasting only for several minutes," said Dr. Parker, "not enough time for the T cell to make new CD40L".
"In a previous study*, we showed that CD4 T cells store a small amount of preformed CD40 ligand in a secretory vesicle inside the cell, and rapidly mobilize it to the cell surface upon antigen recognition," said Yoshinobu Koguchi, MD/PhD, the lead author of the new paper. "Thus, we reasoned that CD4 T cells use this preformed CD40L to help B cells in short encounters, in the same way that killer T cells deliver cytotoxic granules to destroy infected cells."
In their paper, the team successfully distinguished the effects of preformed CD40L from newly made CD40L, and showed that the small amount of preformed CD40L stored in helper T cells is sufficient to activate B cells and dendritic cells in an antigen-specific manner.
"Although the time course is similar, we also showed that helper cells and killer cells use different molecules to deliver the contents of their secretory vesicles to the antigen-presenting cells," said Dr. Koguchi.
"This is an important discovery," said Dr. Parker. "Down the road, identification of the molecular mechanism for the movement of preformed CD40L to the cell surface could provide us with a new molecular target to suppress autoimmune diseases and rejection of transplanted organs while preserving the function of killer T cells."
Picture from left to right: Fanny Polesso; Ellen Makowski, PhD; Yoshinobu Koguchi, PhD; David Parker, PhD; Timothy Thauland, PhD; and Jennifer Gardell.
The Parker Lab Team Members
* Koguchi, Y. et al. 2007. Blood 110: 2520–2527.