Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Eur J Immunol. 2012 Sep;42(9):2343-53. doi: 10.1002/eji.201242501.
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.
B7 家族的配体为 T 淋巴细胞上的 CD28 家族受体提供正向和负向共刺激信号，其平衡决定了免疫反应。B7-H3 是 B7 家族的一员，其在 T 细胞激活中的功能一直存在争议：在自身免疫和肿瘤免疫中，它被描述为共刺激和共抑制，而在移植中，B7-H3 信号被认为有助于移植物排斥。然而，我们现在展示了相反的结果。通过假定的 B7-H3 受体的信号转导延长了完全 MHC 错配的心脏模型中的同种异体移植物的存活期，并促进了向 Th2 环境的转变；相反，通过使用阻断抗体阻断 B7-H3 导致加速排斥，这种效应与 IFN-γ 产生的增强有关。最后，CTLA4 Ig 延长移植物的作用被 B7-H3 阻断和受体 B7-H3 缺失所缩短。这些发现表明 B7-H3 具有共抑制作用。然而，与其他 CD28/B7 家族成员的经验表明，免疫冗余在决定各种途径的功能方面起着至关重要的作用。鉴于存在大量相互矛盾的数据，B7-H3 可能在不同条件下具有正向和负向共刺激功能是合理的。
