Defects and Amplification of Costimulation Across the Species

Abstract

The initiation of a T-cell immune response requires the integration, by the T cell, of signals transduced by numerous cell surface molecular interactions. Central to these is the recognition of an antigenic major histocompatibility complex (MHC):peptide complex by the T cell’s antigen receptor (TCR). Ligation of the TCR leads to signal transduction through the CD3 complex, the signaling component of the receptor. Additional molecular interactions contribute to the elaboration and amplification of the TCR/CD3-transduced signal, which can be referred to as “signal 1.” These include the coreceptors CD8 for MHC class I-restricted T cells and CD4 for MHC class II-restricted cells. Another category of molecules, described as accessory molecules, contributes to the generation of signal 1. These include ICAM- 1, LFA-3, and VCAM1, expressed by the antigen-presenting cell (APC), which interact with LFA-1, CD2, and VLA-4, respectively, expressed by the T cell. These interactions have two functions; first, they increase the avidity of T cell:APC conjugates, thereby increasing the chances of TCR occupancy by specific MHC molecule:peptide complexes. Second, the signals that they transduce amplify signal 1 (Fig. 1). However, it has been long appreciated that the activation of naive and resting memory T cells requires the receipt of a so-called “second,” or “costimulatory,” signal. The two-signal model of T-cell activation was first proposed by Bretscher and Cohn (1), and was substantiated by the work of Jenkins and Schwartz in the mid 1980s (2).