About the Cover
The surface of an antigen-presenting cell (APC) displays a large array of peptides bound to a major histocompatibility molecule (pMHC). Yet, the specific pMHC against which a T cell is directed is often displayed at a very low (i.e., even single digit) copy number among 50,000 to 100,000 other pMHC molecules. These pMHC complexes comprise the same MHC molecule and similarly sized but distinct peptides. How can a T-cell scan and use its T-cell receptor (TCR) machinery to find a "needle in a haystack"? The solution has been achieved through the evolution of the αβ TCR as a mechanosensor. As a result, CD8 cytotoxic T lymphocytes (CTL) and CD4 helperT cells manifest extraordinary ligand sensitivity and specificity. This cover image offers an artist's rendition of MHC molecules projecting from the plasma membrane of an APC. In this case, only one peptide, represented by the small dot in yellow near the periphery of the circle, is the target of that TCR's specificity. Thus, the TCR must mediate T-cell recognition in a chemically complex environment with the ability to finely discriminate among peptides of like size and charge, including tumor antigens for effective elimination of cancers. This figure was rendered by Steve Moskowitz of Advanced Medical Graphics, Boston, MA. For details, see the Masters of Immunology article by Ellis L. Reinherz that begins on page 305 of this issue.

About the Master
Ellis L. Reinherz, MD, is a professor of medicine at Harvard Medical School (HMS) and chief of the Laboratory of Immunobiology and codirector of the Cancer Vaccine Center at the Dana-Farber Cancer Institute (DFCI). Dr. Reinherz is known for his basic research that has revealed key functional and structural discoveries about TCRs, including their CD3 signaling subunit components, and how the TCRs, along with the CD4 and CD8 coreceptor molecules that he identified, bind to the pMHC. More recently he and his colleagues have defined the TCR as an anisotropic mechanosensor, offering a physical solution to the longstanding question of how T cells can achieve rapid and specific sensing of a single peptide bound to an MHC molecule among a sea of unrelated peptides arrayed on the surface of an antigen-presenting cell with exquisite specificity and dynamic range. His findings on the molecular basis of adaptive immunity have implications for rational vaccine design and human immunotherapy efforts in the clinic. He has authored more than 400 research publications in human and murine immunology, spanning areas in basic and translational research. The development of OKT3, the first FDA-approved monoclonal antibody (mAb) in humans, resulted from his studies demonstrating the ability of the mAb to inhibit antigen-specific T-cell responses.

Dr. Reinherz was born in Malden, MA, and is a distinguished alumnus of the Middlesex School in Concord, MA. He entered Harvard College in 1968 and graduated summa cum laude in 1971 with an AB degree. He received his medical degree from HMS in 1975. After completing his internship and residency at the Massachusetts General Hospital and a hematology fellowship at the Brigham and Women's Hospital, Dr. Reinherz pursued research training as a postdoctoral fellow in the laboratory of Stuart Schlossman. Subsequently he was recruited to join the faculty of DFCI and HMS as an assistant professor of medicine, and he has held the rank of HMS professor of medicine since 1994. Dr. Reinherz is a member of the editorial boards of several basic and clinical immunology journals; he is the coeditor of the T-cell biology section of Frontiers in Immunology. Currently he chairs the steering committee of the NIH Human Immunology Project Consortium. Dr. Reinherz is a member of the American Federation for Clinical Research, the American Society of Hematology, the American Society of Clinical Investigation, and the American Association of Immunologists (AAI). He is the recipient of the 2011 AAI Human Immunology Award.