Antigen specific T cell activation by anti-CD3 coated nanoparticles

描述（由申请方提供）：配体-受体相互作用赋予生物学过程特异性。因此，开发特异性激动剂和拮抗剂，即所谓的靶向治疗，提供了选择性抑制或增强生物过程的潜力。 然而，由于特异性受体很少仅在感兴趣的靶细胞上表达，因此靶向治疗的大部分特异性可能丧失。正确的受体可以是特异性靶向的，但不一定仅在感兴趣的细胞上。例如，抗CD 3抗体是激活T细胞受体（TCR）信号级联的有效T细胞激动剂。然而，在体内增强特异性T细胞应答的尝试以继发于一般和非特异性T细胞活化的显著后遗症为标志。抗CD 3的靶点太多。因此，抗CD 3激活T细胞的有效能力尚未被用于增强体内抗病原体或抗肿瘤应答。因此，需要一种增强靶向治疗的选择性以将其限制于感兴趣的细胞的策略。最近，我们的研究小组发现，当抗CD 3抗体被限制在纳米粒子（量子点）的表面时，它选择性地激活先前抗原刺激的T细胞，而不激活幼稚细胞。对特定T细胞的“纳米增强”可能反映了QD/CD 3与抗原刺激的T细胞的聚集TCR的空间匹配，或者可能涉及选择性靶向激活的初始T细胞的其他机制。在该提案中，我们的目标是i）测试量子点上增强的T细胞对抗CD 3应答的机制，ii）设计用于纳米增强的其他新型纳米颗粒，以及iii）测试限制在优化的纳米颗粒上的抗CD 3选择性地增强体内对流感病毒的保护性疫苗应答的能力。

DESCRIPTION (provided by applicant): Ligand-receptor interactions impart specificity to biological processes. Therefore, the development of specific agonists and antagonists, so called targeted therapy, offers the potential of selectively inhibiting or enhancing biological processes. However, since specific receptors are rarely expressed solely on the target cell of interest, much of the specificity of targeted therapy can be lost. The correct receptor may be specifically targeted but not necessarily solely on the cells of interest. For example, anti-CD3 antibodies are potent T cell agonists which activate the T Cell Receptor (TCR) signaling cascade. However, attempts to enhance specific T cell responses in vivo are marked by dramatic sequelae secondary to general and non-specific T cell activation. There are too many targets for anti-CD3. Hence, the potent ability of anti-CD3 to activate T cells has not yet been leveraged to enhance anti-pathogen or anti-tumor responses in vivo. Therefore a strategy to enhance the selectivity of targeted therapy to restrict it to the cells of interest is desirable. Recently, ourgroup has found that anti-CD3, when constrained to the surface of a nanoparticle, a quantum dot, selectively activates previously antigen-stimulated T cells, without activating na¿ve cells. The "nanoboost" to specific T cells may reflect the spatial matching of QD/CD3 to the clustered TCR of antigen-stimulated T cells, or may involve other mechanisms that selectively target activated over na¿ve T cells. In this proposal we aim to i) test mechanisms of the enhanced T cell responses to anti-CD3 on quantum dots ii) engineer other, novel, nanoparticles for nanoboost and iii) test the ability of anti-CD3 constrained on optimized nanoparticles to selectively boost protective vaccine responses to influenza virus in vivo.