A unique feature of the vertebrate immune system is its dependency on the migratory capacity of individual immune cells for proper development, differentiation and functional execution in vivo. High-resolution dynamic live-animal imaging has allowed scientists to decipher novel immunological insights, which is aided by increasing imaging sophistication, availability of in vivo experimental models, and high throughput multi-parameter data collection and analyses. Intravital imaging, combined with mathematical modeling and other immunological tools, has revealed an asymmetric role for MHC interactions in modulating CD4+ vs. CD8+ T lymphocyte surveillance strategies for cognate antigens in lymph nodes (LNs) . Furthermore, naïve CD8+ T cells are preferentially attracted in a CCR5-dependent manner to LN niche sites where cognate antigen recognition occurs between DCs and CD4+ T cells via CCL3 / CCL4 gradient . Additional data suggest that naïve CD8+ T cells regulate transient expression of preformed inflammatory chemokine receptors via integrin engagement early upon entry into inflamed LNs, suggesting a context-specific orchestration of immune responses in LNs.
Once activated in the LNs, T cells travel to various anatomic compartments for delivery of their acquired effector function. Recent imaging experiments revealed that extravascular, CNS-resident CX3CR1+ APCs dynamically extend their cellular processes across intact vessel wall into vascular lumen. The frequency of projections increased in experimental autoimmune encephalomyelitis (EAE), whereas the number of projections remained stable compared to baseline days after other tissue injury such as CNS tumor infiltration and aseptic spinal cord trauma . This unique behavior by CNS parenchymal CX3CR1+ cells may represent their unexplored functional role in antigen sampling and immune cell recruitment across the BBB.
Lastly, we reported a novel role for cyclin-dependent kinase 5 (Cdk5), a proline-directed serine-threonine kinase, in T cell activation and persistence . Cdk5 enzymatic activity has been found to be aberrantly up-regulated in a wide spectrum of tumors. Disruption of Cdk5 activity sensitizes tumor cells to elimination in a T cell-dependent manner, a process that is associated with an attenuated response in PD-L1 up-regulation upon interferon-γ exposure. Our additional emerging data further support a synergistic role of anti-Cdk5 agents in modulating tumor sensitivity to immunotherapeutic approaches.
In conclusion, the tissue microenvironment plays a critical role in regulating host immune cell tumor crosstalk, and recent new advances in imaging modalities and in vivo experimental methodologies provided new insights that hold promises to propel the field of cancer immunotherapy forward.
1. Mandl J. et al. Proc. Natl. Acad. Sci. U.S.A. 2012; 109:18036-18041.
2. Castellino F. & Huang A.Y. et al. Nature 2006; 440:890-895.
3. Barkauskas D.S. & Evans T.A. et al. Microsc. Microanal. 2013; 19:778-790.
4. Pareek TK. et al. J. Exp. Med. 2010; 207:2507-2519.
Citation Format: Alex Yee-Chen Huang. Immunological insights from tracking dynamic cellular behavior in lymph nodes and tissues. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA28.
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