Distantly related members of T cell co-stimulatory pathways

Abstract

Rationale T cell co-stimulatory pathways are critical regulators of T cell activation and tolerance. The B7-1/B7-2:CD28/CTLA-4 pathway is the best characterized of these. The key immunoregulatory role of this pathway has prompted searches for additional B7 and CD28 family members. Several new co-stimulatory pathways in this family have been identified and these have important roles in regulating T cell activation and tolerance. However, the extent of these families and the identities of close relatives in the human genome have not been fully described. Methods We searched the NIH human genome protein database using a new multiple sequence analysis tool of our design. Putative family members were analyzed using structurally-biased multiple sequence alignment and three-dimensional structural models were constructed. Results Novel candidate members and distantly related relatives of the CD28/ICOS/CTLA-4 receptor superfamily and B7/ICOSL ligand superfamily were found. Sequence alignments recapitulated functionally important regions of these families as validated in the co-crystal structures. Conclusions We have identified potentially new members of the B7:CD28 family that may be important for immune activation and tolerance. Multiple sequence alignments and structure modeling demonstrate regions important for protein-protein interactions, and facilitate understanding of the disease-causing role of human polymorphisms.