Focus on high-dimensional analysis of the immune system

Unlike cells of other organ systems whose component proteins are encoded by germline DNA sequences and whose composition remains relatively constant despite environmental fluctuations, cells of the immune system express receptors assembled by random, unpredictable somatic recombination of germline DNA segments; encounters with a pathogen can drive further mutation of these receptors as well as expansion or deletion of the immune cells they decorate. As a result, no two humans have identical immune 'repertoires', and even in the same individual, the immune system will differ markedly over time as a result of infection, aging and disease.

This massive degree of intra- and interindividual diversity constitutes a major technological hurdle blocking detailed characterization and manipulation of the human immune system. The Focus in this issue features a series of articles explaining recent advances in overcoming these technical challenges. But technology is not the only factor hampering progress in the field [Editorial, p. 145 ].

Each individual harbors millions of different B and T lymphocytes, each expressing a distinct receptor. The importance of these receptors cannot be underestimated. B-cell receptors, once secreted, become antibodies responsible for neutralizing pathogens. T-cell receptors (TCRs) recognize and enable killing of microbe-infected cells. Seeking methods to identify and catalog each of these receptors, researchers have turned to DNA sequencing, one of the only existing technologies with throughput sufficient to characterize millions of variables.

George Georgiou, Gregory Ippolito, John Beausang, Christian Busse, Hedda Wardemann and Stephen Quake review the rapidly evolving field of antibody repertoire sequencing, outlining the pros and cons of the various methodologies and highlighting the basic and translational questions that have been and will be answered by these approaches [Review, p. 158 ].

A second piece by Evan Newell and Mark Davis gives an overview of strategies for sequencing TCR repertoires [Review, p. 149 ]. Sequencing is not the end of the story, however, and Newell and Davis describe how new display and cytometry approaches are enabling the identification of T cells expressing receptors specific for antigens of interest.

Especially because high-throughput datasets in immunology are costly and time-consuming to produce, a key goal is to be able to share them among different laboratories. The Human Immunology Project Consortium is working to design standards, repositories and analytical methods needed to make such sharing a routine part of immunological research [Correspondence, p. 146 ].

A major goal of this Focus is to promote dialog between the scientists developing these new technologies and analytical approaches and the immunologists and clinicians asking basic and translational immunological questions. For that reason, we have partnered with our sister journal Nature Immunology in creating the Focus (see Box). Discussion between these two communities will reveal insights into the workings of the human immune system during health and disease, and help design strategies to manipulate it for therapeutic gain. CB & AM