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T cell activation II: Signal integration

Correspondence to: Gary A. Koretzky Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine Abramson Family Cancer Research Institute 415 BRBII/III 421 Curie Blvd Philadelphia, PA 19104 USA Tel.: 215 7465522 Fax: 215 7465525 e-mail: koretzky@mail.med.upenn.edu This is the second of two consecutive volumes examining our understanding of T cell activation. The February 2003 issue of Immunological Reviews explored a number of the membrane proximal events that occur following engagement of the T cell antigen receptor (TCR) or pre-TCR. These signaling pathways are critical for T cell differentiation and proliferation and the development of T cell effector function. The contributors to that volume explored current thinking about the structure of the receptor, how its ligation stimulates three families of protein tyrosine kinases and their downstream signaling pathways, the interplay between tyrosine kinases and tyrosine phosphatases, and how various second messenger cascades are integrated by adapter proteins. The current volume explores a number of other aspects important for T cell activation. While it has long been appreciated that a productive T cell response requires engagement of not only the antigen receptor but also costimulatory receptors, the signaling mechanisms critical for costimulation remain unclear. Thus, although several second messenger cascades have been implicated as essential for costimulation, exactly how signals delivered by the TCR are integrated with those of other receptors (such as CD28) continues to be an area of intense interest by investigators in the field. The first three articles in this issue are devoted to signaling pathways important in T cell costimulation. These papers address the role of second messenger pathways introduced but not discussed in depth in the February issue, including those resulting in the activation of Akt and NF-kB. Additionally, the important issue of whether costimulation merely modulates TCR signaling or, alternatively, induces unique signals is explored in the context of the guanosine triphosphate (GTP) exchanger, Vav. The fourth article in this issue extends the analysis of Vav as a regulator of T cell activation further, with a comprehensive discussion of the complex role played by this protein family in T cell biology. More than two decades ago it was found that phorbol esters are potent stimulators of T cell function. The identification of Immunological Reviews 2003 Vol. 192: 5–6 Printed in Denmark. All rights reserved