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Insights into Immune Cell Matchmaker Protein

Immune cells (white) travel through the blood stream in search of viruses and other foreign agents.

Scientists have identified a protein that plays matchmaker between 2 key types of immune cells, T and B cells, enabling them to establish long-lasting immunity after an infection.

As a B cell travels through the body, it looks for viruses or other foreign agents to engulf. The B cell then displays parts of the foreign agent, called antigens, on its surface. T cells have specialized receptors that can bind to antigens on B cells. Once coupled, the T cells deliver signals to the B cells to multiply and produce antibodies that attack the invader. A critical tissue structure that facilitates these events is the germinal center, which normally forms after an infection within the immune system’s lymph nodes.

Understanding how B and T cells interact in lymph nodes is crucial, because germinal centers are the sites where long-lasting immunity begins. That’s why it was a subject for a collaboration between the laboratories of Dr. Ronald Germain at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Dr. Pamela Schwartzberg at NIH’s National Human Genome Research Institute (NHGRI). Their results appeared in the October 9, 2008, issue of Nature.

The team’s approach stemmed from the fact that the B cells of people with a rare genetic disease called X-linked lymphoproliferative disease (XLP) don’t make antibodies in response to infections and immunizations. As a result, they have an impaired immune response to certain infections, which can prove fatal. People with XLP lack a protein called SAP and don’t have germinal centers. For years, researchers tried to understand the relationship between the absence of germinal centers and the missing SAP protein in XLP patients, but couldn’t identify why the absence of SAP caused these problems.

Using a special microscopy technique that allows direct visualization of immune cells in living mice, the researchers observed how T and B cells and another type of immune cell, the dendritic cell, interact dynamically within mouse lymph nodes. They found that T cells lacking SAP don’t bind strongly to B cells carrying antigens that the T cells would normally recognize.

“The relationship between B and T cells normally is like a pair of dancers,” says Dr. Hai Qi, the lead author. “The B cell leads and the T cell follows in a long tango that eventually goes into the germinal center.”

Without SAP, the tango between the 2 immune cells doesn’t last, and the B cells don’t receive the crucial signals they need to generate functional germinal centers. The SAP-negative T cells, however, did bind to dendritic cells without any problems, even though dendritic cell binding to T cells is similar to that of B cells.

These findings help explain the basis for XLP and provide new insights into the exquisitely specific communications between different types of immune cells. They may also partly explain why some people who can’t make SAP suffer from lethal infections with Epstein-Barr virus, a common virus that otherwise is rarely fatal, and why others have problems with B-cell lymphomas.