Iteratively stimulated T cells as tools to understand mechanisms of nonlymphoid recirculation

Abstract Memory T cell migration facilitates whole-body immunosurveillance and protection against recurrent infections and cancer. In the absence of inflammation, tissue resident memory T cells (TRM) patrol non-lymphoid tissues (NLT) while effector and central memory T cells (TEM and TCM) are mostly restricted to the blood and the blood/lymph system respectively. Memory T cells that retain the ability to recirculate through all compartments are rare and poorly characterized. Thus, the function of these cells as well as their non-lymphoid tissue entry and egress requirements under homeostatic conditions are not well defined. Using a heterologous prime-boost immunization scheme and adoptive transfers, we have generated an abundant murine memory T cell population that has been exposed to >50 viral infections over the last 10 years. We termed these cells iteratively stimulated T cells (ISTCs). Parabiosis experiments revealed that ISTCs acquired pan-migration properties: they can be found in blood, non-lymphoid tissues, lymph nodes, and thoracic duct lymph (TDL) of the naïve parabiont. ISTCs persist in NLTs like the lung which are usually associated with short-lived TRM populations, and mice harboring recirculating ISTCs are protected from lethal Influenza challenge. These data indicate that establishing recirculating memory T cells might provide a new strategy to generate long-lasting immunity in tissues like the lung. Single cell RNA-sequencing revealed tissue entry and egress target molecules that will be tested in in vivoCRISPR-Cas9 screens to elucidate mechanisms of T cell recirculation. Supported by a grant from SNSF P2B-SP3_200187