BioWorld International Correspondent

LONDON - The type of immune response triggered by an antigen is determined at the moment the antigen encounters cells of the immune system, a team of researchers working in Germany has shown.

This new understanding of how the immune system triggers different types of response - whether directed at killing infected cells or leading to antibody production - could lead to more effective vaccines.

Sven Burgdorf, a junior research group leader working in the laboratory of Christian Kurts at the Institute of Molecular Medicine and Experimental Immunology at the Friedrich-Wilhelms University in Bonn, Germany, told BioWorld International: "We have found that the initial antigen uptake mechanism determines what type of immune cells an antigen is presented to, and therefore what type of immune response results. The decision is basically made at the very first point of contact between the immune system and the antigen."

Kurts, Burgdorf and their colleagues report their work in a paper in the April 27, 2007 issue of Science titled: "Distinct Pathways of Antigen Uptake and Intracellular Routing in CD4 and CD8 T Cell Activation."

Antigen-presenting cells, such as dendritic cells, take up antigens in peripheral tissues, and then migrate toward lymphatic organs (such as lymph nodes), where they present the antigens to specialized lymphocytes called T cells.

There are two main populations of T cells, the CD8+ killer T cells and the CD4+ helper T cells. CD8+ T cells are important following a viral infection, as they help to kill virus-infected cells. CD4+ cells help to induce an antibody response, and they can therefore induce an immune response to kill extracellular pathogens, such as most bacteria, directly.

When an antigen-presenting cell ingests an antigen, it breaks it down and "presents" parts of the antigen on its surface, held in the cleft of molecules of the major histocompatibility complex (MHC). If the cell presents the antigen fragment on MHC class I molecules, that can lead to activation of CD8+ T cells. But if the fragment is in an MHC class II molecule, the result is activation of CD4+ T cells.

Burgdorf noted, "Until now, no one has understood what determines whether the antigen is presented on an MHC class I molecule, or whether it is presented on an MHC class II molecule - and therefore what kind of immune response will be generated."

Kurts' team decided to investigate whether the mechanism of endocytosis - the process by which the antigen enters the antigen-presenting cell - played a role in switching the immune response one way or the other.

As the team reported in Science, it found that there was a strict correlation between the type of endocytosis mechanism by which the antigen entered the cell, and the type of T cell that became activated.

The researchers used a model system that involved bone-marrow derived antigen-presenting cells, with albumin protein as their antigen.

They were able to show that if the antigen was taken up by a molecule on the antigen-presenting cell called the mannose receptor, it would enter intracellular compartments they called stable early endosomes; fragments of the antigen would then be presented only on MHC class I molecules, with resulting activation of CD8+ T cells.

If, however, the antigen entered the cell by endocytosis mediated by a molecule called the scavenger receptor, or if it became engulfed by the cell via a process called pinocytosis - a nonspecific way by which extracellular material can enter a cell by being caught up in a fold of its membrane - then it would enter intracellular compartments called lysosomes. After processing, fragments of it would be presented only on class II MHC molecules, and would activate CD4+ T cells.

In each case, the expression of endocytic receptors with an affinity for a specific antigen on antigen-presenting cells determined the route by which the antigen entered the cell and therefore which immune response is induced.

Burgdorf said: "This finding could be applied in the development of vaccines against tumors. It suggests that it should be possible to make vaccines that prime CD8+ T cells to kill tumor cells, by targeting tumor antigens specifically toward the mannose receptor."

Those findings also could help make more efficient vaccines that aim to induce tolerance to particular antigens. "Many auto-immune diseases are mediated by CD4+ T cells, and scientists may be able to adjust the immunization regime so that they can switch off the T-cell reaction and damp down the auto-immune response," Burgdorf said.

Next, the group wants to investigate the mechanisms they have observed in greater detail, and explore ways of applying their findings to help design better vaccines.