Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.

Current success in organ transplantation is dependent upon the use of calcineurin-inhibitor-based immunosuppressive regimens. Unfortunately, current immunotherapy targets molecules with ubiquitous expression resulting in devastating non-immune side effects. T-cell costimulation has been identified as a new potential immunosuppressive target.

Mutational analysis of the CD6 ligand binding domain.

CD6 belongs to the scavenger receptor cysteine-rich protein superfamily (SRCRSF), which includes a large number of cell surface proteins. The extracellular region of CD6 is composed of three SRCR domains. The membrane proximal SRCR domain of CD6 (CD6D3) specifically binds activated leukocyte cell adhesion molecule (ALCAM), a cell surface protein which is a member of the immunoglobulin superfamily (IgSF).

4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.

The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB.

Identification of amino acid residues important for ligand binding to Fas.

The interaction of Fas (CD95), a member of the tumor necrosis factor receptor (TNFR) family, and its ligand (FasL) triggers programmed cell death (apoptosis) and is involved in the regulation of immune responses. Although the Fas-FasL interaction is conserved across species barriers, little is currently known about the molecular details of this interaction. Our aim was to identify residues in Fas that are important for ligand binding.

Mutational analysis of the CD6 binding site in activated leukocyte cell adhesion molecule.

The interaction between CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) mediates adhesion of thymocytes to thymic epithelial cells. The extracellular region of ALCAM includes five Ig-like domains, and its N-terminal V-like domain specifically binds to the membraneproximal scavenger receptor cysteine-rich domain of CD6. Previously, six ALCAM residues were identified by alanine scanning mutagenesis to contribute to the interaction with CD6.