Members of the CD28 family play important roles in regulating T-cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 familymembers. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and Tregs. The nectin-family proteins CD155 and CD112 serve as counter-structures for VSTM3, and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well-characterized CD28-CTLA-4-CD80-CD86 network. In the same way that soluble CTLA-4 can be used to block T-cell responses, we show that soluble Vstm3 attenuates T-cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T-cell responses.

Members of the B7-CD28 family play critical roles in the response of T cells. We have identified the transmembrane protein Vstm3 as a member of the CD28 family based on gene structure. It has two immunoreceptor tyrosine inhibitory motifs in its cytoplasmic domain and is expressed on NK cells and a subset of T cells. Antibodies against VSTM3 antagonize multiple aspects of T cell activation including proliferation and cytokine production indicating it plays an inhibitory role in T cell activation. We have also identified two counter-structures for this protein, the previously identified proteins CD155 and CD112, which are expressed on activated antigen presenting cells. CD155 and CD112 also bind to the activating receptor CD226 and hence this extended family of interacting proteins forms a network of molecules similar to the well characterized CD28-CTLA4-CD80-CD86 network. A soluble form of Vstm3 binds to CD155 and CD112 and disrupts their ability to trigger an activating response through CD226, and hence antagonizes immune responses in vitro and in vivo. On the other hand, an antibody that specifically blocks Vstm3 interaction with CD155 and CD112 tends to enhance T cell responses in vitro and in vivo. Finally, mice that lack Vstm3 are more sensitive to the development of autoimmune diseases. Our data indicate that this novel member of the CD28 family negatively regulates T cell responses.

The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.