Scientists from the National Institutes of Health (NIH) have discovered a new explanation for the flexibility of responses of one type of immune system cell, called T lymphocytes, using a new genome sequencing technology that surveys the cells' epigenomes. The epigenome is the heritable cellular information, other than DNA, which affects phenotype. Their work has generated the largest blueprint of its kind for studying the biology of these cells, and provides new clues about the epigenetic regulation of key immune genes — clues that could one day be used to treat diseases, particularly autoimmune and infectious diseases.
The scientists looked at CD4+ T helper cells, which are vital to the function of the immune system, that protect us against various pathogens. Scientists have known for some time that there are different types of CD4+ T helper cells in the immune system. T helper (TH) type 1 cells help protect against bacteria such as tuberculosis and some viruses. TH2 cells marshal the immune system against invading worms and parasites. TH17 cells defend against other bacteria such as staph (also called Staphylococcus) bacteria, responsible for everything from skin rashes to Toxic Shock Syndrome. Other types of CD4+ T helper cells, called regulatory T cells or Tregs, act as brakes for the immune system, preventing it from attacking the body's healthy tissues, a process that occurs in autoimmune disorders. Co-author William E. Paul, M.D., chief of the Laboratory of Immunology from the National Institute of Allergy and Infectious Diseases (NIAID) said "We know from studying HIV that CD4+ T helper cells are essential in protecting you against disease. In HIV infection, the decline of CD4+ T helper cells is a sign of the onset of AIDS. On the flip side, without cells such as Tregs, the immune system will turn on itself."
Yet, scientists have not entirely understood the biology of these different types of CD4+ T helper cells. Are they firmly fixed according to type like TH1, TH2, TH17, or Treg cells? Or, do they have the opportunity for flexibility or "plasticity" meaning the ability to convert to one another and change their function? The answers could have important implications for medical therapies that aim to increase the ability of T helper cells to either gear up or dampen the immune system's response.
The scientists used a new technology, called ChIP-Seq, which allowed them to survey the modifications of histone proteins, on a genome-wide scale, of all these different types of CD4+ T helper cells in a mouse model. This technology was developed in 2007 in a breakthrough paper in Cell and has been used to explore the immune system by senior author Dr. Keji Zhao, Ph.D., who is a Senior Investigator in the National Heart, Lung, and Blood Institute (NHLBI) Laboratory of Molecular Immunology. "Our genome-wide analysis of histone modifications provides critical information on cell differentiation and gene expression" said Dr. Zhao. Histone modifications are one type of cellular epigenetic regulation, which are inherited changes in genes that occur without a change in DNA sequence. The team especially focused on genes that encode cytokines and transcription factors. Cytokines are secreted proteins that regulate immune cell function, whereas transcription factors bind to DNA and regulate the expression of other genes.
"What we found is that when we looked at some genes, the cells seemed firmly fixed. Yet surprisingly, some master regulators of the cells—the transcription factors—had epigenetic marks that would allow for flexible expression," said study co-author and National Institute of Arthritis and Musculoskeletal and Skin Diseases' Scientific Director John J. O'Shea, M.D. To prove that the cells were changeable or had "plasticity," the scientists treated regulatory T cells with certain proteins or cytokines that they hypothesized could induce changes, and found that they turned into TH1 cells.
The researchers' work has possible implications for medical treatments, because T regulatory cells are now being tested as a therapy for autoimmune disorders. "Our data suggest that depending on the circumstances, Tregs could lose their ability to prevent or treat autoimmune disease, and might start to make inflammatory cytokines instead," Dr. O'Shea said.
The investigators intend to make their extensive genomic data on T helper cells available to scientists worldwide that are interested in studying these cells. Their work outlines a flexible model of T helper cells and an epigenetic mechanism underlying the T cell flexibility. It might also point scientists toward new ways of designing future therapies using T helper cells. "If CD4+ T helper cells are flexible, the challenge now becomes—how can we alter their fates?" said Dr. Paul. "Learning the rules that govern these cells offers us the prospect of being able to manipulate their fates in an appropriate manner to treat disease."
The resulting research, a collaboration among researchers at the NIAMS, the NIAID, and the NHLBI, appears in the current issue of the journal Immunity.
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Wei G, et al. Global mapping of histone H3 K4 and K27 trimethylation reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009;30:155-167.