Suh Woong-Kyung, Wang Seng, Duncan Gordon S, Miyazaki Yoshiyuki, Cates Elizabeth, Walker Tina, Gajewska Beata U, Deenick Elissa, Dawicki Wojciech, Okada Hitoshi, Wakeham Andrew, Itie Annick, Watts Tania H, Ohashi Pamela S, Jordana Manel, Yoshida Hiroki, Mak Tak W
Campbell Family Institute for Breast Cancer Research, 620 University Ave., Suite 706, Toronto, Ontario, Canada.
Mol Cell Biol. 2006 Sep;26(17):6403-11. doi: 10.1128/MCB.00755-06.
Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.
共刺激分子B7家族的成员通过与T细胞上的同源受体结合来调节T细胞增殖和效应功能。体外和体内阻断实验表明，B7-H4（也称为B7S1或B7x）可抑制T细胞的增殖、细胞因子产生及细胞毒性。B7-H4与活化T细胞上表达的未知受体结合。然而，B7-H4在体内是否发挥非冗余的免疫调节作用尚未得到验证。我们构建了B7-H4缺陷小鼠，以研究B7-H4在各种免疫反应中的作用。与其在体外的抑制功能一致，与野生型小鼠相比，B7-H4缺陷小鼠在感染硕大利什曼原虫后，T辅助1（Th1）反应略有增强，寄生虫负荷略有降低。然而，缺乏B7-H4并不影响由Th1或Th2细胞诱导的气道或皮肤超敏炎症反应。同样，B7-H4缺陷小鼠针对病毒感染产生了正常的细胞毒性T淋巴细胞反应。因此，B7-H4在体内发挥负调节作用，但B7-H4缺陷的影响很小。这些结果表明，B7-H4是多种负性共刺激分子之一，它们共同为T细胞介导的免疫反应提供了一种微调机制。
