Researchers have overturned the long-standing notion that lymph nodes are always necessary for launching the mammalian immune response.

Fluorescently-labeled mouse liver Image: Burkhard Becher

According to a study published in this month's issue of PLoS Biology, in the absence of lymph nodes, cell-mediated immunity can be activated in the liver.

The findings undercut immunology "dogma," which says the immune response is always initiated within secondary lymphoid organs, such as lymph nodes and spleen, said Daniel Kreisel, a transplant immunologist at Washington University in St. Louis who did not participate in the study. "This paper shows that T cell-mediated responses can be initiated independent of secondary lymphoid organs."

The assumption that lymph nodes necessarily underlie immunity stems from experiments with mutant mice that lack lymph nodes, known as Alymphoplasia (aly/aly) mutants. These mice fail to display proper antibody and cell-mediated immune responses, a problem which scientists believed stemmed from the missing lymph nodes.

However, neuroimmunologist Burkhard Becher and his colleagues at the Institute of Experimental Immunology in Zurich, Switzerland showed this is not the case. "The mouse doesn't have lymph nodes because it has a mutation," Becher said. "The mutation is the reason for the immunodeficiency."

By transplanting bone marrow from aly/aly mutant mice to wild-type mice, the researchers created chimeric mice that possessed lymph nodes but contained a critical mutation in an immuno-relevant protein, NIFkB-inducing kinase (NIK). These mice were unable to mount an immune response to an injection of Keyhole limpet hemocyanin (KLH) -- a protein found in marine mollusks commonly used as a foreign antigen in animal studies.

Conversely, bone marrow transplants from wild-type to aly/aly mutant mice resulted in chimeras that lacked lymph nodes but produced normal NIK. These mice could, in fact, mount the expected T cell-mediated immune response to KLH.

"We were so stunned by the finding that we looked at several different mouse mutants," Becher said. They validated the finding each time.

The researchers pinpointed the location of the non-lymph immune response by injecting the chimeric mice with fluorescently-labeled microspheres, which accessory immune cells known as antigen-presenting cells carried to the liver.

This finding may be explained by our evolutionary history, Becher said. While "we don't think of it as an immune organ anymore," he said, "the liver is the primary birthplace of our immune system during embryonic development."

Lymph nodes do, however, appear to be necessary for a B cell-mediated immune response, in which antibodies bind to antigens on the surface of pathogens. Again, Becher said, evolution may hold the key to understanding this result. Because T cell-mediated immunity evolved earlier than the modern B cell humoral immune system -- before the evolution of lymphoid structures -- T cells might be expected to be functional outside of the lymphatic system, whereas B cells would not.

"I like the story because it all makes sense in the end," Becher said. "As we were doing it, it didn't make sense at all, [but] it all started to fall into place perfectly."

Correction: We originally listed the new study as coming out in this week's PLoS Biology when in fact it is in this month's issue.


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