Our bodies are frequently exposed to pathogens, including viruses and bacteria, which enter the body through barrier tissues, such as the skin, lungs, and intestine. In response to these infections, specialized immune cells are formed in the barrier tissues, so called tissue-resident memory T cells. These immune cells take up permanent residence in the tissues and act as local guardians against subsequent infections with the same pathogens. Our immune system also offers protection against the development of tumors. In recent years, it has been shown that Trm are important immune cells that can clear tumor cells. These Trm develop at the site of the tumor, where they will remain permanently to optimally support anti-tumor immune responses. In order to develop immunotherapies that employ Trm to counter infection or tumor growth, it is essential to understand how these memory T cells can be expanded in vivo or in vitro, but, currently, it is unclear where, when and how Trm develop. Therefore, we designed an in vivo mouse model that allowed us to specifically visualize Trm using a fluorescent marker that exclusively labeled Trm, but not circulating T cell lineages. Using this model system, we were able to trace the developmental pathway of Trm that is initiated in draining lymph nodes and is completed in the peripheral tissues, where tumors arise. We discovered that Trm almost completely separated from circulating T cell lineages at early stages of the immune response. Characterization of these early Trm precursors showed that they lacked an important molecular regulator known as Eomes. Interestingly, Eomes could suppress the development of Trm precursors and their offspring. Therefore, Eomes appears to be an important factor that steers developing T cells into the direction of circulating memory T cells rather than Trm. Our findings suggest that targeting of Eomes might be an important strategy to increase the number of Trm at the tumor site for the purpose of immunotherapy of cancer patients.
It was also unknown how Trm contribute to successful immune responses against pathogens and tumors. Immune responses against a secondary encounter with a pathogen are faster than the initial response, but the reasons for this have long been incompletely understood. We have found that the T cells in the tissue quickly reacted to reinfection and expanded locally. This enabled an accelerated immune response that started directly in the infected tissue instead of the lymph nodes. Surprisingly, some of the local T cells also left the tissue and moved into the bloodstream in response to the reinfection. Hereby, these former tissue-resident T cells contributed to immune responses throughout the body. Importantly, these tissue-experienced T cells persisted in the blood long after the pathogen was cleared. As these T cells were trained in the tissues, they may provide enhanced protection by mounting tissue-tailored immune responses. Indeed, we found that the T cells in the blood with a history of tissue residence provided improved protection against a subsequent infection. Thus, our results suggest that during a second infection with a pathogen, the immune response initiates within the tissue and then extends throughout the body. This process shapes the immune repertoire, and may adapt our immune system to more efficiently respond to invading pathogens. Given that novel cancer therapy approaches rely on the responses of T cells from (tumor) tissues, our findings may also have important implications in the context of cancer treatment, in particular adoptive cell therapy.