Ludwig Institute for Cancer Research

New Haven, Connecticut (August 29th)—Researchers at Yale University and the Ludwig Institute for Cancer Research have captured on video the rather difficult journey a group of immune stimulating molecules go through to warn the body of potential threats, according to a study in the August 29th issue of Nature.

Using an advanced filming method, a team led by Dr. Ira Mellman watched as activated dendritic cells rummaged through a type of cellular trash bin, known as the lysosome, to salvage unused major histocompatibility complex class II (MHC II) molecules. These molecules bind with antigen fragments and then present the material on the dendritic cell surface, where they prompt immune defenses to launch an attack. Exactly how the MHC II molecules make it out of the lysosome trap has long been a mystery.

The video shows dendritic cells generating special tubule-shaped cargo containers that can then transport the molecules and antigen fragments to the cell surface. By capturing the action live on tape, the study documents a pathway that could only be guessed at before.

“We have had all sorts of theories on why dendritic cells behave in certain ways, but at the end of the day, you want to see them in action,” said Dr. Mellman, who is with the department of cell biology and section of immunobiology at Yale University School of Medicine, and an affiliate at the Ludwig Institute for Cancer Research. “Visualizing how cells work can provide for remarkably creative insights.”

The ability to rescue MHC II molecules from lysosomes is yet another special feature that researchers are now finding out about dendritic cells, an ever vigilant cadre of sentinels that, when stimulated by bacterial invaders, shuttle substances to the top of cells so that the immune system can recognize the danger. Understanding how dendritic cells initiate immune responses to microbes may eventually lead to new ways to treat disease.

For example, disorders such as arthritis and Crohn’s disease result from overactive immune cells attacking healthy tissue. Cancer, on the other hand, often goes unrecognized by the immune system, allowing tumors to spread. In both cases, dendritic cells may be a key target for promoting more favorable immune responses.

As part of the study, Dr. Mellman’s team infected dendritic cells with bacteria so that the cells would mature and become active. They then filmed both stimulated and unstimulated dendritic cells through a technique known as confocal video microscopy. Of the 15 unstimulated dendritic cells, only two grew tubules that could potentially transport MHC II cells from lysosomes. In contrast, all 50 or so of the stimulated dendritic cells showed dynamic tubule development.

The team went on to demonstrate that the tubules from stimulated dendritic cells fused with plasma membrane found on the surface of cells, evidence that MHC II molecules once destined for obscurity could be rescued and put to use.

“There are still a number of outstanding questions on how this transport system works,” said Dr. Mellman. “But these issues can now be easily addressed through similar experiments using live cell imaging.”

In fact, a new treatment for arthritis and Crohn’s disease may work by inhibiting the ability of dendritic cells to rescue intracellular MHC II. Dr. Mellman points out that fully understanding this pathway has some very direct implications: His own son is currently undergoing successful treatment for Crohn’s disease that follows the same principle.

“Do I want to understand how this process works?” Dr. Mellman asked. “You bet I do.”

By Eric Sabo

Abstract

Chow A, Toomre D, Garrett W, Mellman I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature. 2002 Aug 29;418(6901):988-94. [PMID: 12198549]