Viral infections and cancer are examples of diseases that would greatly benefit from the improvement of therapeutic vaccines. The lack of effective treatments for many types of these diseases makes the development of such vaccines a priority and its elaboration is an area of active interest as evidenced by the great number of ongoing clinical trials. In the realm of vaccine development and design, the primary achieved effect is the potent induction of humoral immune responses. However, the use of vaccines to eradicate cancers and some pathogens will require the generation of robust cell-mediated immunity, particularly CD8 T-cell responses. Currently, numerous clinical trials are trying to develop therapeutic vaccinations against cancer and a common process of interest is the efficient antigen presentation to T cells. Naturally, dendritic cells have become an important component of vaccine design due to their excellent antigen presentation capacity. In particular, CD8 conventional dendritic cells (cDCs) are of the utmost importance in this process due to their critical role in cross-presentation and their potent ability to induce cytotoxic T-lymphocyte effector activity and memory formation. Nevertheless, in spite of their importance, the mechanism by which these cells develop is unknown, limiting our capacity to selectively expand the CD8 cDC population. However, recent findings in our laboratory are helping us to understand this process. We have identified genetic background differences amongst mouse strains that will provide us with the necessary tools for the identification of a CD8 cDC committed progenitor. In turn, we will be able to perform a novel genetic profiling and comparison of progenitors with different cDC developmental potential in order to identify the transcription factor circuitry responsible for the development of both branches of cDCs. Previously our laboratory showed that the Batf3-/- mice lack CD8 cDCs. Interestingly, we have identified a Batf3-dependent Irf8 binding cis-element in the promoter of Irf8, a critical transcription factor for the development of CD8 cDCs. Thus, we aim to test if the Irf8 expression maintenance of the CD8 cDCs depends on the Irf8-Batf3 complex binding in such cis-element. Such discoveries will help us understand the cDC differentiation mechanism so that therapeutic targeted expansion of CD8 cDCs can be developed for the improvement of vaccine design.
Driving cell mediated immune responses is the critical issue the effectiveness of vaccines against cancers and intracellular pathogens. CD8 T cells responses to viruses and tumors requires a process known as cross-presentation, in which exogenous antigens are delivered to a dendritic cell, but loaded onto MHC class I molecules to allow activation of CD8 T cells, the killer cells of the adaptive immune system. Dendritic cells ar not a single type of cell within the immune system but develop into several subsets, and one of these known as the CD8+ DC is the most potent in the cross-presentation pathway. Mice lacking this DC subset were made by the Murphy lab, the Batf3-deficient mouse line, and this has shown the critical role of CD8+ DCs not only in many types of viral infection but also in anti-tumor immunity. However, this DC subset is typically a very small fraction of all DCs but the Murphy lab has shown can be expanded to great effectiveness during certain infections, through an unknown mechanism. The project outlined in this training application will bring new basic understanding of the regulation of the development of DC8+ DCs which we know can directly improve anti-tumor responses. Therefore there can be a real translational benefit to the basic information we seek.
|BriseÃ±o, Carlos G; Haldar, Malay; Kretzer, Nicole M et al. (2016) Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells. Cell Rep 15:2462-74|
|Murphy, Theresa L; Grajales-Reyes, Gary E; Wu, Xiaodi et al. (2016) Transcriptional Control of Dendritic Cell Development. Annu Rev Immunol 34:93-119|
|Grajales-Reyes, Gary E; Iwata, Arifumi; Albring, JÃ¶rn et al. (2015) Batf3 maintains autoactivation of Irf8 for commitment of a CD8Î±(+) conventional DC clonogenic progenitor. Nat Immunol 16:708-17|