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.
The ability to selectively activate T cells using antibody-covered quantum dots could potently enhance individual responses to vaccines and could also extend stores of available vaccine when there is not enough vaccine to cover the entire population at risk. In addition, besides enhancing vaccines of proven efficacy, nanoboost might be able to improve the efficacy of vaccines in development, to infectious agents such as malaria, HIV and Hepatitis C and could also increase the efficacy of anti- tumor vaccines.
| Lo, Ying-Chun; Edidin, Michael A; Powell, Jonathan D (2013) Selective activation of antigen-experienced T cells by anti-CD3 constrained on nanoparticles. J Immunol 191:5107-14 |
