IMMUNOBIOLOGY OF HYBRID RESISTANCE

描述(改编自《调查者摘要》)：对骨的排斥 小鼠和其他物种的骨髓移植在很大程度上是由 杀手细胞。尽管拒绝是非常具体的，但有一个重大的 移植遗传学规则的例外，即F1杂交小鼠(或 大鼠)可以排斥亲本品系的骨髓移植(杂交抗性)。NK 细胞缺乏在发育过程中重排的T或B细胞受体基因。 相反，NK细胞表达自身和其他I类抗原的受体； 大多数情况下，这些受体会收到不杀死目标的负面信号。 细胞。主要受体基因家族为Ly49，位于第6号染色体上，靠近 NKR-P1家族的NK受体基因。Ly49和NKR-P1分子都是 II以同源二聚体形式存在的完整膜蛋白。一种免疫调节剂 位于细胞质区域的酪氨酸抑制基序(ITIM)是 对负面信号负责。两名家庭成员，Ly49D 和H，缺少ITIM；Ly49D接收激活信号。共同表达的 Ly49D和负信号Ly49受体不应该被杀死，因为 负面信号占主导地位。这项提案的目标是确定如何 这些NK细胞受体调节骨髓移植的排斥反应。目标1： 确定Ly49C和Ly49I NK细胞受体在移植排斥反应中的作用 血型不合的骨髓移植。需要检验的两个假设：1)等位基因形式 ITIM+Ly49C和Ly49I受体和I类抗原都是关键 不同品系的NK细胞识别靶细胞的能力； 这种能力也受到这些基因的选择性使用的调节；2) 转基因B6小鼠Ly49I基因的表达可改变小鼠的免疫功能 小鼠拒绝骨髓移植。目标2：确定 NK细胞的ITIM-Ly49D亚群排斥骨髓移植 I类抗原。要检验的两个假设：1)Ly49D的等位基因形式 将调节NK细胞排斥I类异基因骨髓的能力 嫁接。B6的Ly49D基因向FVB“差”小鼠的转移 拒绝者“将赋予他们排斥这种骨髓移植的能力；2) Ly49D NK细胞对自身I类抗原产生耐受性 通过共表达ITIM+Ly49受体也识别 自身抗原。目的3：分析Ly49-NK细胞失效的机制 排斥异基因骨髓移植。需要检验的两个假设：1)Ly49-NK 细胞在骨髓细胞上接受来自大多数I类AGS的负信号；2) NK细胞的非Ly49受体，如NKR-P1B(10A7)，是ITIM+的 缺乏Ly49+细胞，除了那些不识别“自我”类的细胞 我。

DESCRIPTION (Adapted from Investigator's abstract): The rejection of bone marrow grafts in mice and other species is mediated largely by natural killer cells. Although the rejection is highly specific, there is a major exception to the rules of transplantation genetics, i.e., F1 hybrid mice (or rats) can reject parental-strain marrow grafts (hybrid resistance). NK cells lack T or B cell receptor genes that rearrange during development. Rather, NK cells express receptors for self and other class I antigens; for the most part, these receptors receive negative signals not to kill target cells. The major receptor gene family is Ly49, on chromosome 6 near the NKR-P1 family of NK receptor genes. Both Ly49 and NKR-P1 molecules are type II integral membrane proteins that exist as homodimers. An immunomodulatory tyrosine-based inhibitory motif (ITIM) located in the cytoplasmic domain is responsible for the negative signaling. Two members of the family, Ly49D and H, lack the ITIM; Ly49D receives activation signals. Co-expression of Ly49D and a negative signaling Ly49 receptor should not kill because the negative signal dominates. The goal of this proposal is to determine how these NK cell receptors regulate rejection of marrow grafts. Aim 1: Determine the role of Ly49C and Ly49I NK cell receptors in rejection of incompatible marrow grafts. Two hypotheses to test: 1) the allelic forms of ITIM+ Ly49C and Ly49I receptors and class I antigens are both critical for the ability of NK cells of various strains to recognize target cells; this ability is also regulated by selective use of these genes; 2) expression of Ly49I gene of B6 mice as a transgene can alter the ability of mice to reject marrow grafts. Aim 2: Determine the mechanism by which the ITIM- Ly49D subsets of NK cells reject marrow grafts differing by particular class I antigens. Two hypotheses to test: 1) the allelic form of Ly49D will regulate the ability of NK cells to reject class I allogeneic marrow grafts. Transfer of the Ly49D gene of B6 to FVB mice that are "poor rejectors" will endow them with the ability to reject such marrow grafts; 2) Ly49D NK cells develop "tolerance" to self class I antigens during development by co-expressing ITIM+ Ly49 receptors that also recognize the self antigen. Aim 3: Analyze the mechanisms by which Ly49- NK cells fail to reject allogeneic marrow grafts. Two hypotheses to test: 1) Ly49- NK cells receive negative signals from most class I Ags on marrow cells; 2) non-Ly49 receptors of NK cells, e.g., NKR-P1B (10A7), that are ITIM+ are lacking on Ly49+ cells except for those that do not recognize "self" class I.