Role of NKG2 Family Receptors in Regulating the Immune Response

必须严格调节免疫反应，一方面避免低反应性，另一方面避免过度炎症和自身免疫（高反应性）的发展。这种平衡至少部分是通过抑制信号对激活信号的抑制来实现的。理想情况下，这导致了对入侵者的充分免疫反应，没有过度和延长的炎症信号，促进自身免疫的发展。CD94NKG2受体家族由具有激活或抑制潜能的成员组成。这些受体主要在NK细胞和CD8 T细胞亚群上表达，它们已被证明在调节对感染和致瘤细胞的反应中发挥重要作用。我们的研究探索了这些受体生物学的各个方面，包括配体和受体相互作用、信号传导、膜动力学和基因表达调控。我们目前的重点是在细胞生物学和分子水平上了解CD94NKGA抑制受体如何以显性方式失活激活受体产生的信号，以及该受体通过何种机制运输以保持在细胞表面的持续存在。

Immune responses must be tightly regulated to avoid hyporesponsiveness on one hand or excessive inflammation and the development of autoimmunity (hyperresponsiveness) on the other. This balance is at least partially attained through the throttling of activating signals by inhibitory signals. This ideally leads to an adequate immune response against an invader without excessive and extended inflammatory signals that promote the development of autoimmunity. The CD94NKG2 family of receptors is composed of members with activating or inhibitory potential. These receptors are expressed predominantly on NK cells and a subset of CD8 T cells, and they have been shown to play an important role in regulating responses against infected and tumorigenic cells. Our studies explore all aspects of the biology of these receptors, including ligand and receptor interaction, signaling, membrane dynamics, and regulation of gene expression.Our current emphasis is to understand, at the cell biology and molecular levels, how the the CD94NKGA inhibitory receptor inactivates signals generated by activation receptors in a dominating manner and by what mechanism this receptor traffics so as to maintain constant presence on the cell surface. The exact means by which inhibitory signals obviate activation signals in immune cells are not totally elucidated. Human CD94NKG2A is an ITIM containing inhibitory receptor expressed by NK cells and some CD8 T cells that recognizes HLAE. We showed that the engagement of this receptor prevents NK cell activation by disruption of the actin network and exclusion of lipid rafts at the point of contact with its ligand (inhibitory NK cell immunological synapse, iNKIS). CD94NKG2A engagement leads to recruitment and activation of src homology 2 domain bearing tyrosine phosphatase 1. This likely explains the observed dephosphorylation of guanine nucleotide exchange factor and regulator of actin, Vav1, as well as ezrinradixinmoesin proteins that connect actin filaments to membrane structures. In contrast, NK cell activation by NKG2D induced Vav1 and ezrinradixinmoesin phosphorylation. Thus, CD94NKG2A prevents actin dependent recruitment of raft associated activation receptors complexes to the activating synapse. These data indicate that the lipid rafts exclusion at the iNKIS is an active process which requires an intact cytoskeleton to maintain lipid rafts outside the inhibitory synapse. The net effect is to maintain an inhibitory state in the proximity of the iNKIS, while allowing the formation of activation synapse at distal points within the same NK cell.