Intact B7-H3 signaling promotes allograft prolongation through preferential suppression of Th1 effector responses.
Ligands of the B7 family provide both positive and negative costimulatory signals to the CD28 family of receptors on T lymphocytes, the balance of which determines the immune response. B7-H3 is a member of the B7 family whose function in T-cell activation has been the subject of some controversy: in autoimmunity and tumor immunity, it has been described as both costimulatory and coinhibitory, while in transplantation, B7-H3 signaling is thought to contribute to graft rejection. However, we now demonstrate results to the contrary. Signaling through a putative B7-H3 receptor prolonged allograft survival in a fully MHC-mismatched cardiac model and promoted a shift toward a Th2 milieu; conversely, B7-H3 blockade, achieved by use of a blocking antibody, resulted in accelerated rejection, an effect associated with enhanced IFN-γ production. Finally, graft prolongation achieved by CTLA4 Ig was shortened both by B7-H3 blockade and the absence of recipient B7-H3. These findings suggest a coinhibitory role for B7-H3. However, experience with other CD28/B7 family members suggests that immune redundancy plays a crucial role in determining the functions of various pathways. Given the abundance of conflicting data, it is plausible that, under differing conditions, B7-H3 may have both positive and negative costimulatory functions.
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Takuya
T
Ueno
Melissa Y
MY
Yeung
Martina
M
McGrath
Sunmi
S
Yang
Nadia
N
Zaman
Benjamin
B
Snawder
Robert F
RF
Padera
Ciara N
CN
Magee
Rostic
R
Gorbatov
Masaaki
M
Hashiguchi
Miyuki
M
Azuma
Gordon J
GJ
Freeman
Mohamed H
MH
Sayegh
Nader
N
Najafian
D000069594:Abatacept; D000818:Animals; D060887:B7 Antigens / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014181:Transplantation Immunology; D014184:Transplantation, Homologous / Q000276:immunology*
D060887:B7 Antigens; D018106:CD28 Antigens; C486038:Cd276 protein, mouse; D018796:Immunoconjugates; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept; D007371:Interferon-gamma