T-cell costimulatory blockade in organ transplantation

Abstract

Before it became possible to derive T-cell lines and clones, initial experimentation on the activation requirements of T lymphocytes was performed on transformed cell lines, such as Jurkat. These studies, although technically correct, proved misleading as most transformed T cells can be activated by stimulation of the clonotypic T-cell receptor (TCR) alone. In contrast, once it became possible to study nontransformed T cells, it quickly became clear that TCR stimulation by itself is insufficient for optimal activation of naïve T cells, but in fact, induces a state of anergy. It then became clear that functional activation of T cells requires not only recognition of major histocompatibility complex (MHC) and peptide by the TCR, but also requires ligation of costimulatory receptors expressed on the cell surface.

Figure 1.

Costimulatory molecules and proximal signaling components. Immunoglobulin superfamily (top) and TNF superfamily receptors (bottom) expressed on T cells are shown on the left. Ligands are depicted in the antigen-presenting cell (APC) on the right. Dotted lines represent receptor–ligand pairs. Signaling motifs within the cytoplasmic tails are indicated in blue rectangles. Black circles represent phosphorylatable tyrosines. Proteins that interact directly with the cytoplasmic tails of costimulatory molecules are shown. Details of the signal transduction proteins are described in the text.