The cells of the immune system, and lymphocytes in particular, have a wide spectrum of programme choices when faced with stimuli such as invading pathogens. Making the right choices can save lives, whereas inappropriate, unstable or poorly regulated responses can be costly and result in disease susceptibility, autoimmunity or immune pathology. For these reasons, lymphocytes are good model systems to study cell lineage choice and the regulation of gene expression. In addition to transcription factors, lineage choice and gene regulation are controlled by epigenetic mechanisms: modifications that do not alter the sequence of DNA, but rather change the chemical properties of DNA (for example by methylation of specific cytosine residues) or the composition and post-translational modifications of proteins, RNA and other molecules that package DNA into chromatin. The power of epigenetic mechanisms is illustrated by the ability of pathogens to subvert host defences by undermining epigenetic mechanisms. In view of our growing understanding of epigenetic mechanisms, now is a good time to consider what epigenetics can teach us about the workings of the immune system. This is why we have asked a number of illustrious researchers in immunology, haematology and epigenetics to join forces with Immunology to publish a series of reviews with a focus on epigenetic control of host defence.
The first four articles in this series appeared in the June issue of Immunology (Volume 139:2): Pierre Ferrier and colleagues discussed how epigenetic mechanisms shape the repertoire of T-cell and B-cell receptors – central to the development and function of the adaptive immune system – by controlling the rearrangement of lymphocyte antigen receptor genes. Taku Naito and Ichiro Taniuchi reviewed how T-cell lineage decisions are directed by repressive epigenetic marks such as DNA methylation, histone deacetylation and the methylation of histone H3 lysine 9 (H3K9me) and by Polycomb repressive complexes. In a highly informative vignette, George Lacaud and colleagues described the role of the acetyltransferase MOZ (monocytic leukaemia zinc finger) in haematopoiesis. The gene encoding MOZ is often translocated in acute myeloid leukaemia, linking post-translational histone modifications to cell fate decisions and cancer in the haematopoietic system. Conny Bonifer shared her personal thoughts about why, despite the availability of genome-wide approaches, it can still be rewarding to dedicate time and effort to the detailed study of specific gene loci.
The cover of the current issue (designed by Vladimir Ramirez-Carrozzi) shows a view of the chromatin landscape from the perspective of Steve Smale and his colleague Vladimir Ramirez-Carrozzi. The promoters of inducible genes often contain CpG-islands that are accessible to transcriptional regulators because they generally exhibit a low density of nucleosomes. This chromatin state facilitates rapid transcriptional induction by a broad range of stimuli so that the immune system can respond rapidly and come to the defence of the host. Continuing along these lines, Sudha Rao and colleagues review how inducible gene expression in the immune system is regulated at the epigenetic level, focusing on the interleukin-2 gene Il2 as a key example of an inducible gene in T cells that is critical for immunity and tolerance, and regulated by several layers of transcriptional and epigenetic control.
During an immune response, the first waves of inducible gene expression are followed by the formation of immune effectors, which provides a unique view of the mechanisms used by CD4 T cells to make lineage decisions as they differentiate into specialized helper and regulatory T-cell subsets. This theme is taken up both by Golnaz Vahedi, John O'Shea and colleagues and by Steve Josefowicz, who recently moved his focus from regulatory T cells (with Sasha Rudensky) to histone modifications and now works with leading epigenetics researcher David Allis. Building on one of the most exciting recent discoveries in the epigenetics field, both reviews communicate the concept of a ‘division of labour’ between the transcription factors that coordinate the differentiation of CD4 T cells. A key question is how to establish, maintain and propagate transcriptional enhancers that set apart specialized CD4 T-cell subsets. This is because these enhancers control lineage-specific patterns of gene expression, including T helper lineage-specific signature cytokines and factors that control regulatory T-cell function. Surprisingly, the well-known, lineage-specific transcription factors Gata3, T-bet, RorγT or Foxp3 are not the players that break new ground here. On the contrary, the establishment of new enhancers appears to be the job of less highly specialized factors that respond to extracellular signals such as cytokines. In comparison to these pioneers, the lineage-specific factors look like opportunists that occupy new enhancers only once they are already set up. In their vivid and gripping tour of epigenetic landscapes in T helper cell subsets, O'Shea and colleagues keep a sharp focus on enhancers. Armed with the take-home messages, readers will enjoy the detailed view of chromatin states offered by Josefowicz, including his account of the activity of Foxp3 in regulatory T cells, the timeline of T helper type 17 differentiation,[13, 14] and the intricacies of composite transcription factor binding sites.
Once the immune system has gained the upper hand over an infection, a key decision is the choice between effector and memory cell differentiation. In their review, Rafi Ahmed and colleagues Ben Youngblood and Scott Hale focus on the transcriptional and epigenetic regulation of key immune effector genes in naive, effector and memory cells. They explain the importance of genes that control T-cell homing and survival for the development of effector memory and central memory T-cell differentiation, discuss how epigenetic modifications may help to preserve ‘poised’ transcriptional states in memory cells, and explore the mechanisms that result in a loss of transcriptional plasticity in antigen-specific T cells that experience sustained high levels of T-cell receptor signalling.
We are very excited about introducing these specially commissioned articles to the readership of Immunology and hope that they will inspire new ideas and great experiments on the epigenetic control of host defence.