Spotlight on Research 2009

May 2009 (historical)

NIAMS Researchers Identify a Protein that Helps Govern Immune Cell Differentiation

Scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health, have discovered that the protein Lyn kinase, expressed in immune cells called basophils, helps control the way immune cells called T helper cells differentiate in mice. This ability to govern cell differentiation makes basophils and their cell-signaling pathways possible targets for future therapeutic strategies in systemic lupus erythematosus (SLE) and other immune-mediated diseases. The study recently appeared in the journal Immunity.

T helper cells are so-called because they help other immune cells respond to attacks. Specifically, they identify threats to the immune system, then activate and govern other cells that mount a defense. Cell differentiation is the process by which naive T cells become more specialized and direct other cells.

A healthy immune system requires a balance of specialized T helper 1 (Th1) and Th2 cells, and the Th1-Th2 balance is maintained through cell differentiation. During response to infection, naive T cells may differentiate into Th1 or Th2 cells, depending on the infectious agent. However, if the ratio of Th1 to Th2 cells is skewed too much toward one type or the other, then the body's immune response can go awry.

Scientists have known that basophils play an important role in T helper cell differentiation. What the NIAMS team, led by Juan Rivera, Ph.D., acting chief of the NIAMS Laboratory of Molecular Immunogenetics, wanted to understand was how basophils exerted that control.

In mice engineered to have a complete Lyn deficiency, the NIAMS researchers discovered that basophils expressed high levels of a transcription factor (a protein that controls the expression of genes) called GATA-3, which results in the production of interleukin-4, a protein that promotes differentiation of naive T cells into Th2 cells. In normal mice, the presence of Lyn kept basophils from over-expressing GATA-3, which in turn prevented the overproduction of Th2 cells.

In the Lyn-deficient mice, the NIAMS team found that the over-representation of Th2 cells did, in fact, cause inappropriate immune responses. When the mice were exposed to albumin, a normally inert substance, they developed allergies to it. Moreover, when they were exposed to a known allergen, they developed early onset of the Th2 differentiation, as well as enhanced Th2-cell responses. Interestingly, in late-life these mice developed a SLE-like disease with kidney involvement.

While Th2 cells are protective against some parasites, bacteria, and viruses, they are also known to cause allergic diseases. However, little is known about their role in other diseases. Rivera says his team is excited to see how Lyn's ability to shift the balance toward Th2 cells might be relevant to SLE and other autoimmune diseases.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at 301-495-4484 or 877-22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Charles N, Watford WT, Ramos HL, Hellman L, Oettgen HC, Gomez G, Ryan JJ, O'Shea JJ, Rivera J. Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation. Immunity. 2009;30(4):533-543.