Immunology

Edited by: Eugene Russo T CELL STARTER: Harvard's Michael Grusby believes that research on Stat pathways will lead to a better understanding of T cell differentiation. M.H. Kaplan, U. Schindler, S.T. Smiley, M.J. Grusby, "Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells," Immunity, 4:313-9, 1996. (Cited in more than 75 publications as of February 1998) Comments by Michael J. Grusby, Department of Immunology and Infectious Diseases, Harvard School of Public Health Sometimes good cells turn bad. When produced at the wrong time, T helper cells, which are meant to fight off harmful antigens, can end up attacking the molecules, cells, and tissues that they're suppose to be defending, thereby causing autoimmune diseases. Potential therapies for such disorders may entail the manipulation of the cell pathways that lead to T helper cell differentiation. Scientists have attempted to do so by identifying the molecules involved in those pathways. One such molecule is Stat6, one of seven recently identified Stat (signal transducer and activator of transcription) proteins responsible for mediating the biological responses to a variety of different growth factors, cytokines, and hormones. Only Stat6 is activated in response to interleukin-4 (IL-4), a cytokine well known for its effects on the immune system. IL-4 activates B and T lymphocytes and facilitates the differentiation of T helper 2 (Th2) cells, a subset of cells that assist T and B cells. In order to determine the role of the Stat6 signaling pathway in mediating IL-4 function, the authors of this paper, along with teams from Osaka University (K. Takeda et al., Nature, 380:627-30, 1996), and St. Jude Children's Hospital in Memphis, Tenn. (K. Shimoda et al., Nature, 380:630-3, 1996), produced Stat6-deficient mice. "What we were able to demonstrate is that [Stat6] is indeed the functionally important signaling pathway for mediating most . . . of the biologic responses to IL-4," reports senior author Michael Grusby, an associate professor of molecular immunology at Harvard School of Public Health and an associate professor of medicine at Harvard Medical School. "And importantly, the Stat6 pathway is the one that leads to the differentiation of Th2 cells." In a subsequent paper (M.H. Kaplan et al., Nature, 382:174-7, 1996), the Harvard team, working again with the research team from St. Jude Children's Hospital, demonstrated that disruption of the Stat4 gene, another of the Stat family members, impairs the differentiation of Th1 cells much as the absence of the Stat6 protein impairs the differentiation of Th2 cells. "The Stat4- and the Stat6-deficient mice represent the best available models for looking at the role of Th1 or Th2 cells in various immune responses," reports Grusby. His lab has put this model to use with soon-to-be published research into the development of allergic asthma in Stat6-deficient mice. Stat6-deficient animals not able to generate Th2 cells do not exhibit much of the pathophysiology associated with the development of allergic asthma. These findings suggest that intervention at the level of Stat6 may be an effective therapy. Grusby attributes the paper's popularity in part to the usefulness of this Stat6 mouse model. He also cites general interest in T helper cell subsets, which are integral to proper immune responses and are therefore of great importance in immunology and associated fields. His team is effectively working its way down the molecular pathway that culminates in T cell differentiation. "Up until this observation, the only other effective molecule where one would be able to potentially intervene would be at the level of the cytokine, which would be IL-4," he explains. "But disrupting IL-4 function is going to disrupt a whole variety of downstream functions." According to Grusby, better, more appropriate treatments may be possible by intervening at the level of Stat6. Grusby's group and others continue to study the Stat pathway. "Now what we're trying to do is to identify the downstream genes that get activated in response to Stat6, [the ones] that actually do the driving of the differentiating of the Th2 cells," he says.

Immunology

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