T-cell costimulation--biology, therapeutic potential, and challenges.

n engl j med 10.1056/nejmp068087 is tightly regulated to prevent autoreactivity. The processes of T-cell activation and self-tolerance are therefore potential targets for manipulation by drugs — hence, the recent phase 1 trial of a “superagonistic” monoclonal antiCD28 antibody that was conducted in Britain on behalf of the German firm TeGenero, with unexpected and devastating results that are described in the report by Suntharalingam et al. in this issue of the Journal. T-cell activation requires two signals that are delivered by antigen-presenting cells (APCs) (see figure). The first signal is antigen displayed by APCs in the form of peptides bound to histocompatibility molecules; the recognition of antigen by T-cell receptors provides specificity to the response. The second signal, called the “costimulatory signal” because it stimulates T cells in conjunction with antigen, is provided by molecules on APCs that engage particular costimulatory receptors on T cells. In the absence of costimulation, T cells that recognize antigen either fail to respond and die or enter a state of unresponsiveness known as anergy. Thus, costimulation is a key determinant of the outcome of a T cell’s encounter with antigen. The best-characterized T-cell costimulatory pathway involves the CD28 receptor, which binds to two costimulatory molecules, B7-1 (CD80) and B7-2 (CD86).1 CD28 is constitutively expressed on all T cells in mice and on 95% of CD4+ T cells and 50% of CD8+ T cells in humans. B7-1 and B7-2 are expressed mainly on APCs, including dendritic cells, macrophages, and B cells. The expression of B7-1 and B7-2 on APCs is enhanced by the presence of microbes and by cytokines that are produced in response to microbes. This regulated expression of B7 costimulators ensures that T cells respond best only when necessary — that is, when faced with pathogens. The interaction of B7-1 and B7-2 with CD28, in concert with T-cell–receptor signaling, promotes the expansion of antigenstimulated T cells and their differentiation into effector and memory cells. CD28 is the major costimulatory receptor for naive T cells and is therefore important for initiating T-cell responses. CD28 signals enhance the proT-Cell Costimulation — Biology, Therapeutic Potential, and Challenges