B7-H5 costimulates human T cells via CD28H

The B7/CD28 family has profound modulatory effects in immune responses and constitutes important targets for the development of novel therapeutic drugs against human diseases. Here we describe a new CD28 homolog (CD28H) that has unique functions in the regulation of the human immune response and is absent in mice. CD28H is constitutively expressed on all naive T cells. Repetitive antigenic exposure, however, induces a complete loss of CD28H on many T cells, and CD28H-negative T cells have a phenotype of terminal differentiation and senescence. After extensive screening in a receptor array, a B7-like molecule, B7 homolog 5 (B7-H5), was identified as a specific ligand for CD28H. B7-H5 is constitutively found in macrophages and could be induced on dendritic cells. The B7-H5/CD28H interaction co-stimulates human T cell growth and cytokine production, selectively via an AKT-dependent signaling cascade. Our study identifies a novel co-stimulatory pathway regulating human T cell responses.