Featured Article - February 2012
Short description: A novel immunoglobulin ligand with functions in autoimmunity and cancer surveillance is characterized.
Regulatory control of the immune system is achieved by interactions between receptors and ligands, which function together to initiate the immune response while limiting autoimmunity. Immunoglobulin family members are therefore critical for T cell activation and cytokine production, and operate as part of a balanced signaling network.
Noelle and colleagues (PSI IFN and NYSGRC) describe the discovery and functional characterization of VISTA, a novel suppressor of T cell activation. Using microarray analysis, the authors identified an unknown gene product in activated T cells with homology to Ig superfamily members. Sequence analysis indicated that VISTA contains a canonical extracellular Ig-V domain in addition to transmembrane and cytoplasmic segments.
BLAST analysis revealed that VISTA is closely related to the immunoglobulin B7 family member PD-L1, which was used as a template to construct a model of the VISTA Ig-V domain. The model of the Ig-V domain contains five invariant cysteine residues and a long loop inserted between the C′′ and D β-strands. The authors suggest that these five cysteines will likely give rise to a novel disulfide-bonding pattern in VISTA when compared to those present in other immunoglobulins. These predicted structural features and the presence of only one extracellular domain places VISTA in a unique category of the Ig superfamily.
The authors found that VISTA expression is tightly regulated during the active immune response in transgenic mice. Using RT-PCR and flow cytometry, they determined that VISTA expression mainly occurs in hematopoietic cells and is highly expressed on antigen-presenting cells (APCs) and CD4+ T cells. While increased expression was observed on APCs during an inflammatory immune response, the authors note that, in contrast, VISTA expression was decreased on CD4+ cells. They speculate that the cytokine microenvironment may down-regulate VISTA expression on activated T cells, although the functional significance of expression on CD4+ cells is currently unknown. Experiments in a mouse model for multiple sclerosis provided further evidence that VISTA is an inhibitory ligand in vivo and engages an as yet unidentified receptor. The unique expression patterns and predicted structural features make VISTA a potential target for the treatment of autoimmunity, viral infection and cancer.
L. Wang et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses.
J. Exp. Med. 208, 577-592 (2011). doi:10.1084/jem.20100619