B.J. Fowlkes

MHC Class II–Specific T Cells Can Develop in the CD8 Lineage When CD4 Is Absent

The generation of mature CD4 T cells from CD4+CD8+ precursor thymocytes usually requires corecognition of class II MHC by a TCR and CD4, while the production of mature CD8 T cells requires corecognition of class I MHC by a TCR and CD8. To assess the role of the CD4 coreceptor in development and lineage commitment, we generated CD4-deficient mice expressing a transgenic class II-specific TCR. Surprisingly, in the absence of CD4 a large number of T cells mature, but these cells appear in the CD8 lineage. Thus, when CD4 is present, the majority of immature T cells with this class II-specific TCR choose the CD4 lineage but develop in the CD8 pathway when CD4 is absent. The results indicate that even for TCRs that are not dependent on coreceptor for MHC recognition, the coreceptor can influence the lineage choice. These findings are considered in terms of a quantitative signaling model for CD4/CD8 lineage commitment.

Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4(+) T cells.

The transcription factors GATA-3 and ThPOK are required for intrathymic differentiation of CD4+ T cells, but their precise functions in this process remain unclear. Here we show that, contrary to previous findings, Gata3 disruption blocked differentiation into the CD4+ T cell lineage before commitment to the CD4+ lineage and in some contexts permitted the redirection of major histocompatibility complex class II–restricted thymocytes into the CD8+ lineage. GATA-3 promoted ThPOK expression and bound to a region of the locus encoding ThPOK established as being critical for ThPOK expression. Finally, ThPOK promoted differentiation into the CD4+ lineage in a way dependent on GATA-3 but inhibited differentiation into the CD8+ lineage independently of GATA-3. We propose that GATA-3 acts as a specification factor for the CD4+ lineage upstream of the ThPOK-controlled CD4+ commitment checkpoint.

Expression of genes of the T-cell antigen receptor complex in precursor thymocytes

The antigen receptor on Tlymphocytes has recently been characterized as a heterodimeric, transmembrane glycoprotein consisting of disulphide-linkedα(acidic) and β (basic) subunits of relative molecular mass (Mr) 40,000–45,000 each. The genes encoding these proteins have been cloned1–4 and shown to resemble immunoglobulin genes in both overall structure and the requirement for DNA rearrangement before expression5–11. In humans, three additional proteins, termed the T3 complex, are found associated with the clonotypic receptor, and a role for T3 in receptor expression has been proposed12–15. Despite these recent advances in characterizing the antigen receptor complex, there is as yet little understanding of T-cell maturation, particularly the stage of T-cell ontogeny at which the genes encoding the antigen receptor and its associated structures are expressed and assembled. In the adult, stem cells destined to differentiate into T cells arise in the bone marrow and migrate to the thymus16, where T-cell precursors proliferate, develop a preference for recognizing antigens in the context of self MHC molecules17,18and are released to the periphery. Recently, cells that have the properties of immature murine thymocytes have been isolated and described19,20. We have now analysed these cells with a series of molecular probes and we describe three distinct patterns of T-cell antigen receptor gene rearrangements in developing thymocytes.

The influence of the thymic environment on the CD4-versus-CD8 T lineage decision

T cell receptor signaling is an essential factor regulating thymocyte selection, but the function of the thymic environment in this process is not clear. In mice transgenic for major histocompatibility complex class II–restricted T cell receptors, every thymocyte is potentially selectable for maturation in the CD4 lineage. To address whether selection frequency affects positive selection, we created hematopoietic chimeras with mixtures of selectable and nonselectable precursors. With increased proportions of nonselectable thymocytes, positive selection of MHC class II–specific precursors was enhanced, generating not only CD4 but also CD8 thymocytes. These results indicate that the CD4 versus CD8 fate of selectable precursors can be influenced by the selection potential of its neighbors.

Casting a Wider Net

With this issue of Immunity, editorial responsibility for the journal has shifted once again. Immunity was nurtured through its early days by colleagues at Harvard and MIT and ably guided through its growth to the present day by others at Washington University and Yale. All of us owe a debt of gratitude to the previous editors for the outstanding job they did to ensure that the content of Immunity was of the highest quality and was drawn from the best the field had to offer. As a result of their efforts, we inherit a journal that is one of the premier venues for publication of immunological research. Our responsibility is to maintain these high standards while ensuring that the journal remains compatible with the changing landscape of immunological research and scientific publication.The contents of a journal such as Immunity reflect to some degree the taste and research interests of the Editors. Fortunately, prior editorial committees have shown excellent judgment and the journal has consistently published outstanding work in immunology, especially at the molecular level. We intend to maintain this tradition of excellence in the publication of molecular analyses of immunological phenomena while at the same time encouraging authors to submit their most creative and insightful work across the broadest possible range of topics. New approaches to the analysis of the human immune system, advances in the immunology of infectious and inflammatory diseases as well as cancer, and applications of mathematical modeling to immune analysis are just some examples of subdisciplines that we hope will be increasingly represented in the pages of Immunity.The decision about publication of a particular submission will be made as it has been for years, with reliance on reviews by referees well versed in the subject of a submission and careful consideration of these reports by the entire Editorial Board. A new feature of the journal will be electronic submission. The switch from hard copy submission and the elimination of the ensuing rounds of express package delivery will help speed up the review process and also allow more facile computer tracking of manuscripts and reviews. We also anticipate that the new system will permit referees to see the other reviews of a paper once their own comments are submitted. This exposure to the comments of others that have carefully considered the same manuscript should help raise the high level of reviewing for Immunity even further.Another area in which there will be changes is review articles. As immunology becomes more complex and fragmented into subdisciplines, the need for accessible reviews has grown. In recognition of the need for all of us to keep abreast of developments outside of our specific areas of expertise, many review journals have emerged recently to supplement the major publications on which we have all relied for many years. Cell Press believes that Immunity would serve its readers well by including more reviews in its pages, both brief commentaries (“Previews”) tied to primary papers appearing in the journal and full or mini-reviews on topics in which new paradigms have emerged or large amounts of new data have been published. Responsibility for the latter articles will be in the hands of a separate group of Reviews Editors, while the Previews will be commissioned by us based on papers accepted for publication. The Reviews Editors will also select reviewers and handle evaluation of all papers with an NIH author, to avoid any potential conflicts of interest.We thought long and hard about accepting the difficult and time consuming task of serving as the Editors of Immunity. In the end, it was clear to us that we owed a debt of gratitude to past editors and had a responsibility to the field that could be best recognized by taking on this responsibility. We also saw it as an exciting prospect that would expose us to a broad range of research in immunology, with the editorial board meetings becoming a welcome forum for scientific discussions with valued colleagues. These positive aspects of the work far outweighed the difficult task of getting permission from NIH to act in this capacity, permission that requires us to divorce our service for Immunity from our laboratory activities. One restriction imposed on us in this regard is that we cannot use U.S. Government facilities for our editorial responsibilities, which means that author contact with the Editors (which we hope will be necessary only rarely) must be via Cell Press and not our NIH phones or e mail. The details of this arrangement will be in the Instructions to Authors in the journal and on the Immunity web pages. We think this should be of little consequence in the broader scheme of things and look forward to providing the immunological community with editorial service that sustains the tradition of excellence that has characterized the previous boards of Immunity.

William E. Paul, M.D. (1936–2015)

Science is a tapestry made from many small threads of information. When these strands are woven together in the right order, they produce images revealing the underlying patterns of the natural world. A few select scientists are not merely contributors of these threads, but are weavers of the tapestry, giving form and meaning to the pieces of information they and others contribute.