Vaccines have been a hugely successful public health intervention, virtually eliminating many once common diseases of childhood. However, they have had less success in controlling endemic pathogens including
Mycobacterium tuberculosis
, herpesviruses and HIV. A focus on vaccine-mediated generation of neutralizing antibodies, which has been a successful approach for some pathogens, has been complicated by the emergence of escape variants, which has been seen for pathogens such as influenza viruses and SARS-CoV-2, as well as for HIV-1. We discuss how vaccination strategies aimed at generating a broad and robust T cell response may offer superior protection against pathogens, particularly those that have been observed to mutate rapidly. In particular, we consider here how a focus on generating resident memory T cells may be uniquely effective for providing immunity to pathogens that typically infect (or become reactivated in) the skin, respiratory mucosa or other barrier tissues.
Bunkered in barrier tissue, tissue-resident memory T (T RM ) cells are strategically positioned to react quickly to tissue perturbations, such as infection, injury, or cancer. Recent studies have highlighted a potential role for T RM cells as a targetable T cell population due to their abundance in most tissues. To better understand the role T RM cells play in the antitumor immune response, we developed a targeted CRISPR screen to identify the essential genes regulating the T RM -response to tumors. We first developed a murine tumor model system in which OT-I cells could be adoptively transferred and re-isolated from tumors. Yumm1.7 tumor cells were transduced with OVA fused to mCherry. SIINFEKL reactivity to Yumm.OVAmCh tumors was confirmed by pentamer staining, ELISPOT, and OT-I proliferation in vivo. To promote T RM -responses we used a model of skin scarification where tumors develop in the uppermost layers of the skin. In this model, approximately 1/3 tumors are spontaneously rejected. On day 7 after tumor inoculation, skin-residing T cells expressed CD103 and CD69, which was not observed in tumors engrafted subcutaneously. Further, CD8 + T cells isolated from the skin of rejected tumors contained SIINFEKL-reactive T RM cells. Next, we optimized T cell transduction to achieve approximately 20% efficiency, which was enriched to 50% after puromycin selection. Finally, to achieve statistically powerful guide-RNA (gRNA) coverage we chose to target select genes expressed in T RM cells and CD8 + tumor-infiltrating lymphocytes (TILs). To this end, we compared gene expression profiles of T RM cells and TILs across several studies. From this cross-study comparison, we chose both up-and down-regulated genes (log2 fold-change > 1.5) totaling 1,469 genes. In conclusion, the epicutaneous tumor model system provides a vehicle to study T RM -responses to melanomas. Future studies will apply a targeted-deletion OT-I T cell library to these tumors to reveal genes critical for the T RM -response to tumors.
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