Behar S M, Porcelli S A, Beckman E M, Brenner M B
Department of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
J Exp Med. 1995 Dec 1;182(6):2007-18. doi: 10.1084/jem.182.6.2007.
A class of molecules that is expressed on antigen presenting cells, exemplified by CD80 (B7), has been found to provide a necessary costimulatory signal for T cell activation and proliferation. CD28 and CTLA4 are the B7 counterreceptors and are expressed on the majority of human CD4+ T cells and many CD8+ T cells. The signal these molecules mediate is distinguished from other costimulatory signals by the finding that T cell recognition of antigen results in a prolonged state of T cell unresponsiveness or anergy, unless these costimulatory molecules are engaged. However, nearly half of the CD8+ and CD4-CD8- T cells lack CD28, and the costimulatory signals required for the activation of such cells are unknown. To understand the pathways of activation used by CD28- T cells, we have examined the costimulatory requirements of antigen-specific CD4-CD8- TCR(+)-alpha/beta circulating T cells that lack the expression of CD28. We have characterized two T cell lines, DN1 and DN6, that recognize a mycobacterial antigen, and are restricted not by major histocompatibility complex class I or II, but by CD1b or CD1c, two members of a family of major histocompatibility complex-related molecules that have been recently implicated in a distinct pathway for antigen presentation. Comparison of antigen-specific cytolytic responses of the DN1 and DN6 T cell lines against antigen-pulsed CD1+ monocytes or CD1+ B lymphoblastoid cell lines (B-LCL) demonstrated that these T cells recognized antigen presented by both types of cells. However, T cell proliferation occurred only when antigen was presented by CD1+ monocytes, indicating that the CD1+ monocytes expressed a costimulatory molecule that the B-LCL transfectants lacked. This hypothesis was confirmed by demonstrating that the T cells became anergic when incubated with the CD1(+)-transfected B-LCL in the presence of antigen, but not in the absence of antigen. The required costimulatory signal occurred by a CD28-independent mechanism since both the CD1+ monocytes and CD1+ B-LCL transfectants expressed B7-1 and B7-2, and DN1 and DN6 lacked surface expression of CD28. We propose that these data define a previously unrecognized pathway of costimulation for T cells distinct from that involving CD28 and its counterreceptors. We suggest that this B7-independent pathway plays a crucial role in the activation and maintenance of tolerance of at least a subset of CD28- T cells.
一类表达于抗原呈递细胞上的分子，以CD80（B7）为代表，已被发现可为T细胞活化和增殖提供必要的共刺激信号。CD28和CTLA4是B7的反受体，表达于大多数人CD4⁺ T细胞和许多CD8⁺ T细胞上。这些分子介导的信号与其他共刺激信号的区别在于，除非这些共刺激分子参与其中，T细胞对抗原的识别会导致T细胞无反应状态或无能的延长状态。然而，近一半的CD8⁺和CD4⁻CD8⁻ T细胞缺乏CD28，此类细胞活化所需的共刺激信号尚不清楚。为了解CD28⁻ T细胞所使用的活化途径，我们研究了缺乏CD28表达的抗原特异性CD4⁻CD8⁻ TCR(+)α/β循环T细胞的共刺激需求。我们鉴定了两个T细胞系，DN1和DN6，它们识别一种分枝杆菌抗原，不受主要组织相容性复合体I类或II类限制，而是受CD1b或CD1c限制，CD1b和CD1c是主要组织相容性复合体相关分子家族的两个成员，最近被认为参与了一条独特的抗原呈递途径。比较DN1和DN6 T细胞系对抗原脉冲处理的CD1⁺单核细胞或CD1⁺ B淋巴母细胞系（B-LCL）的抗原特异性细胞溶解反应表明，这些T细胞识别这两种细胞呈递的抗原。然而，只有当抗原由CD1⁺单核细胞呈递时T细胞才会增殖，这表明CD1⁺单核细胞表达了一种B-LCL转染细胞所缺乏的共刺激分子。通过证明T细胞在有抗原存在的情况下与CD1(+)转染的B-LCL孵育时会变成无能状态，而在无抗原时则不会，这一假设得到了证实。所需的共刺激信号通过一种不依赖CD28的机制产生，因为CD1⁺单核细胞和CD1⁺ B-LCL转染细胞都表达B7-1和B7-2，而DN1和DN6缺乏CD28的表面表达。我们提出，这些数据定义了一条以前未被认识的T细胞共刺激途径，不同于涉及CD28及其反受体的途径。我们认为，这条不依赖B7的途径在至少一部分CD28⁻ T细胞的活化和耐受性维持中起关键作用。
