B7x negatively regulates the immune response in peripheral tissues

Abstract

The B7 family of proteins provides regulatory signals that can either costimulate or coinhibit T cells during both activation and effector phases. B7x is a coinhibitory member of this family whose currently unknown receptor is expressed on activated T cells and existing data show that its mRNA expression is highest in peripheral non-lymphoid tissues. We detected B7x protein expression in the lung, pancreas and other non-lymphoid tissues, but not in any lymphoid tissues. To investigate the role of B7x in a tissue where its protein is expressed, we tested the outcome of a pulmonary infection model in B7x knockout (B7x-/-) mice by infecting intranassally with a lethal dose of Streptococcus pneumoniae. Following challenge, B7x-/-, but not wild-type (Wt), mice exhibited a resistant phenotype with significantly lower bacterial burdens, reduced inflammatory cytokines, and milder immunopathology in lungs. Resistance in B7x-/- mice was associated with an increase in activated CD4 and CD8 T cells and lower numbers of neutrophils, while the opposite cellular profile was observed in the susceptible Wt mice. To better understand B7x coinhibition of T cells we set up a system to examine its effect on antigen-specific effector CD8 T cells in an in vivo mouse model. To do this we activated OT-I OVA-specific CD8 T cells ex vivo and adoptively transferred them into mice that overexpress B7x and OVA (RipB7x/OVA.Tg) or just OVA (OVA.Tg) in their pancreatic 13-islets. The functional consequence of B7x overexpression on the effector CD8 T cells was that although they were in contact with their target beta-cells, they did not destroy them and the RipB7x/OVA.Tg mice had a significantly lower incidence of diabetes than the OVA.Tg mice. We find that B7x inhibits T cell function in peripheral tissues and that in the context of infection its absence is protective due to an enhanced T cell response, whereas in autoimmunity it presence is protective as it curtails a damaging T cell response. Our data support B7x as an important ways that the immune system is able to maintain a balanced response so that while pathogenic entities are effectively eliminated, autoimmunity and immunopathology are prevented.