About the Cover
The thymus is required for the generation of a normal adaptive immune system; thymocyte development and selection are essentially complete prior to sexual maturity. T cells that leave the thymus can recognize peptides presented by the body's class I or class II major histocompatibility complex (MHCI/II). The ordered stages of intrathymic T-cell development include double negative (DN; CD4−CD8−) → double positive (DP; CD4+CD8+) → transitional (CD4+CD8low) → CD8+ T-killer cells or CD4+ T-helper cells. T-cell receptors for MHCI/II (TCRI or TCRII) are expressed on DP thymocytes, which are selected upon encounter with the appropriate MHC molecules. DP cells with TCRs that are not selected for binding to the body's peptides plus MHCI/II die from “neglect” in the cortex. Thymocytes with too high an affinity
for peptides plus MHCI/II die from “negative selection” in the cortex and medulla. In a healthy person, only ∼2% of newly generated thymocytes exit the thymus daily; the rest die in situ during various stages of development. If the transitional (CD4+CD8low) thymocyte expresses TCRII, interaction with CD4 and MHCII will activate transcription factor Th-POK to generate CD4+ T-helper cells. If the transitional (CD4+CD8low) thymocyte expresses TCRI, the weak binding of TCRI and downregulated CD8 with thymic MHCI in the presence of IL7 will cause coreceptor reversal, i.e. the cell expresses transcription factor RUNX3, which silences the transcription of CD4 and antagonizes Th-POK, enabling the development of CD8+ T-killer cells. For details of thymocyte development, see the Masters of Immunology primer by Harald von Boehmer on page
592 of this issue.
About the Master
Harald von Boehmer, MD, PhD, is a professor emeritus at the Dana-Farber Cancer Institute (DFCI) and Harvard Medical School (HMS), an adjunct professor at the University of Florida, and a visiting professor in the Institute for Immunology at the Ludwig-Maximilian University of Munich, Germany, where he received his MD in 1968. He subsequently earned a PhD in 1974 from the University of Melbourne, Australia, under the tutelage of Dr. Ken Shortman. Dr. von Boehmer was a member of the Basel Institute for Immunology in Switzerland until 1996, before becoming the director of Unité INSERM 373 at the René Descartes University in Paris, France. He was recruited to join the faculty at DFCI-HMS in 1999, where he served as chief of the Laboratory for Lymphocyte Biology in the DFCI Department of Cancer Immunology and AIDS and a faculty member of the HMS Department of Microbiology and Immunobiology.
The von Boehmer laboratory has contributed significantly to our understanding of T-cell development and its roles in immune responses. Dr. von Boehmer discovered the pre-TCR, cloned the pre-TCRα gene, and defined its role in TCRβ allelic exclusion. Using gene transfer of the TCR, he characterized TCR contribution to recognition by T cells of peptide–MHC complexes. Through analysis of TCR transgenic mice, his favorite experiments, he delineated the role of negative selection in the thymus of developing T cells by peptide–MHC complexes to generation of self-tolerance. He elucidated mechanisms of positive selection in intrathymic generation of CD8+ killer cells, CD4+ helper cells, and FoxP3-expressing CD4+ regulatory cells. His studies on TCR-signaling pathways that permit conversion of naïve T cells into regulatory T cells in vivo have been used to establish antigen-specific tolerance to insulin and prevention of type 1
diabetes. He described the contribution of T-cell development to acute lymphoblastic T-cell leukemia. In particular, his studies of TCR signaling and Notch signaling revealed that T-cell lineage commitment is instructed by the intensity of TCR signals, and that Notch signaling is mandatory for the generation of αβ but not γδ lineage T cells.
Dr. von Boehmer was born in Guben, Germany; he is an accomplished cellist and has performed with orchestras in Goettingen and Freiburg. His many honors include the Louis-Jeantet Prize for Medicine, jointly with Nicole Le Douarin and Gottfried Schatz (1990), the Avery-Landsteiner prize of the German Society for Immunology (1990), the Paul Ehrlich and Ludwig Darmstadter Prize for Immunology (1993), the Kurt A. Korber Prize for European Science (1997), and most recently the Helmholtz International Fellow Award (2013). He also received an honorary medical degree from the Technical University of Munich (2002). Dr. von Boehmer is an elected member of the Academia Europaea (1990), the Institut Universitaire de France (1997), and the German Academy of Sciences Leopoldina (2003).