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PATHOLOGY Molecular Agent Prepares Immune ForcesStudy Could Lead to More Broadly Effective Therapies for Autoimmune Diseases A diagram showing how the immune system responds to a foreign invader would be a patchwork of crisscrossed lines punctuated by question marks. One of the critical gaps is understanding the nature of the CD28 and CTLA-4 pathway—a variable cascade critical to infection fighting by T cells. Now a group of researchers led by Arlene Sharpe has characterized one of the recently identified players in this pathway, yielding information that could lead to better therapeutic control of T cell activity in people with autoimmune diseases and other disorders.
Rebecca Greenwald, Gordon Freeman, Arlene Sharpe, and Alex McAdam (l to r) have characterized a new player in an immune pathway that influences the way T cells fight infection. Photo by Graham Ramsay For a T cell to be fully activated, it needs two signals. The first is initiated by a foreign antigen along with a T cell receptor, and the second by a co-stimulatory molecule. Without the costimulatory signal, which is independent of the antigen, the T cell would abort activation. The CD28 and CTLA-4 receptors on T cells are bound by the costimulatory molecules B7-1 and B7-2, expressed on antigen-presenting cells. These molecules provide a critical signal for stimulating the T cell response when they bind the CD28 receptor and, on the contrary, for inhibiting the response when they bind CTLA-4. Because of these pronounced effects, the B7-CD28/CTLA-4 pathway has been the subject of intense research on downstream target and effector molecules. There also is great interest in co-stimulation because of its therapeutic potential, said Sharpe, an associate professor of pathology at Brigham and Women's Hospital. Preventing costimulation provides a way to manipulate the immune system without having to tailor therapy to a specific antigen or T cell receptor. According to Sharpe, a variety of clinical trials—several in the HMS community—aim at blocking the B7-CD28 pathway. Animal models have shown that altering the pathway can treat autoimmune diseases, transplant rejection, and allergic disorders. The ConnectionIn the Jan. 4 Nature, Sharpe and her colleagues, including postdoctoral fellows Alex McAdam and Rebecca Greenwald and collaborator Gordon Freeman, assistant professor of medicine at the Dana–Farber Cancer Institute, demonstrate in a murine knockout model that the inducible costimulatory (ICOS) receptor, a CD28 homologue, is important for T helper cell differentiation and the T cells' role in B cell antibody production. The receptor, first reported in January 1999, is expressed on T cells following their activation. "The inducible expression of ICOS suggested that manipulation of the ICOS pathway might provide a means to intervene during an immune response after T cells have been activated, which is when patients with autoimmune diseases are seen," said Sharpe.The ligand for ICOS, which has five different names because it has been reported by five different groups, is most commonly called B7h. This molecule is not only expressed on antigen-presenting cells like B cells, dendritic cells, and macrophages, but also on other cell types such as fibroblasts and epithelial cells. Building a Case The first paper on ICOS from McAdam, Sharpe, and Freeman showed that B7-CD28 interactions upregulate ICOS. Seeing this led to the hypothesis that CD28 exerts some of its effect by ICOS upregulation. B7-CD28 signaling promotes T cell activation by stimulating a range of effects: interleukin-2 production, T cell proliferation and survival, and T helper cell differentiation, particularly of the T helper 2 type. The pathway supports the T and B cell collaboration necessary for antibody class switching and formation of germinal centers, sites in the lymph node or spleen where T and B cells interact. ICOS upregulates another costimulatory molecule, CD40-Ligand. Expressed on T cells, CD40L interacts with CD40 on B cells to effect antibody class switching. To Sharpe, that was a clue that CD28 exerts its effects on T and B cell collaboration through ICOS. "Could ICOS act downstream of B7-CD28 to have an effect on T and B cell collaboration through CD40L expression?" In the current study, Sharpe tested her hypothesis by generating mice that lack ICOS. She found that these knockouts have defects in the T and B cell collaboration necessary to make isotype-switched antibodies and to form germinal centers. It seems that the ICOS pathway upregulates CD40L to enable the CD40–CD40L interactions that are critical for antibody class switching. Sharpe demonstrated this by triggering CD40 signaling with antibodies in the ICOS-deficient mice. "We wanted to see whether we could circumvent this defect if we gave these mice a stimulatory anti-CD40 antibody. And the answer is that we could," she said. The ICOS-deficient mice also exhibit altered T helper cell differentiation. Differentiation of CD4+ T helper cells into T helper 1 or T helper 2 subsets, each associated with different cytokines, has profound effects on the outcome of autoimmune diseases, infectious diseases, and graft rejection. Sharpe has found that the stimulation of ICOS leads to increased production of the cytokines interleukin-4 and interleukin-10, and its loss leads to increased interferon-gamma production. "IL-10 seems to be a key immunosuppressive cytokine, so ICOS stimulation might be a way to suppress autoimmune disease. On the other hand, you could try to block ICOS when there's undesired T helper 2 responses such as occur in allergy and asthma. We find that the ICOS-deficient mice are defective in class switching to the IgE antibody that is important in asthma," she said. The next step for Sharpe is to study different types of disease models in vivo to understand where the ICOS pathway is important. —Tracy Hampton |
