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Distantly related members of T cell co-stimulatory pathways
S54 Abstracts
SATURDAY
113
Distantly Related Members of T Cell Co-stimulatory Pathways
M. J. Butte1, A. H. Sharpe2, R. S. Geha1; 1Division of Immunology, Children’s Hospital Boston, Boston, MA, 2Department of Pathology, Brigham and Women’s Hospital, Boston, MA. 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. Funding: Children’s Hospital Boston
J ALLERGY CLIN IMMUNOL FEBRUARY 2004
SATURDAY
113
Distantly Related Members of T Cell Co-stimulatory Pathways
M. J. Butte1, A. H. Sharpe2, R. S. Geha1; 1Division of Immunology, Children’s Hospital Boston, Boston, MA, 2Department of Pathology, Brigham and Women’s Hospital, Boston, MA. 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. Funding: Children’s Hospital Boston
J ALLERGY CLIN IMMUNOL FEBRUARY 2004