Scientific Report 2005

Immunology

Control of Cytokine Expression by Arginine Methylation

K.A. Mowen, J.W. Fathman

Helper T cells can be divided into 2 distinct populations on the basis of their immune specificity and cytokine profiles. Type 1 helper T cells produce IFN-γ and are responsible for cell-mediated immunity; type 2 helper T cells secrete IL-4 and are associated with the humoral immune response. These 2 types of cells have been associated with susceptibility to malignant, infectious, allergic, and autoimmune diseases. The improper development of type 2 helper T cells can lead to allergy and asthma, and an overactive response by type 1 helper T cells can lead to autoimmune diseases such as type 1 diabetes.

Because of the opposing roles of the 2 types in immune function, the development and migration of helper T cells must be tightly regulated. Indeed, the discrete subsets, type 1 and type 2, reciprocally antagonize the maturation and behavior of each other in the immune response, resulting in a population of helper T cells that is primarily type 1 or type 2. Thus, manipulating the ratio of type 1 to type 2 helper T cells provides an intriguing avenue of therapy, and understanding the molecular events that control lineage-specific cytokine expression may provide useful tools to modulate the helper T cell response.

Although several lineage-specific and nonspecific transcription factors are required for the development and function of type 1 and type 2 helper T cells, less is known about the events that occur after the reactivation of type 1 and type 2 effector populations and result in the disparate cytokine profiles of the 2 types of helper T cells. Signal transduction pathways use posttranslational modifications to translate changes in the extracellular milieu into environment-sensitive gene expression in a timely and efficient fashion.Phosphorylation of serine, threonine, and tyrosine residues and protein ubiquitination have been widely studied. Although methylation of arginine residues was discovered more than 30 years ago, it has only recently aroused renewed interest. Arginine methylation of proteins by members of the protein arginine methyltransferase (PRMT) family regulates the subcellular localization of the methylated proteins and modulates protein-protein interactions.

We discovered a unique contribution of arginine methylation to cytokine gene expression downstream of signaling by T-cell receptors. Our goal is to investigate more broadly the role for arginine methylation in immune function, including further study of helper T cells and other immune cell types. We also plan to examine the upstream regulation of PRMT expression and activity and characterize the effects of ablation or suppression of PRMT expression. Understanding the role of posttranslational modifications, such as arginine methylation, of proteins that are key in regulating cytokine production will give us novel targets in diseases induced or exacerbated by the cytokine environment, such as inflammatory arthritis.