The right microbial stimulus can direct innate immune effector cells to specific organ sites to clear pathology

Abstract

25Recent developments in understanding how the functional phenotype of the innate immune system 26 is programmed has led to paradigm-shifting views on immunomodulation. These advances have 27 overturned two long-held dogmas: only adaptive immunity confers immunological memory and 28 innate immunity lacks specificity. This work describes the novel observation that innate immune 29 effector cells can be recruited to specific tissues of the body where pathology is present by using 30 a microbial-based immune stimulus that consists of an inactivated pathogen that typically resides 31 or causes infection in that target tissue site. We demonstrate this principle using experimental 32 models of cancer and infection for which different subcutaneously delivered microbial-based 33 treatments were shown to induce the recruitment of immune effector cells to specific diseased 34 organs. Amelioration of disease in a given organ niche was dependent on matching the correct 35 microbial stimulus for the affected organ site but was independent of the nature of the pathology. 36 This observation intriguingly suggests that the immune system, upon pathogen recognition, tends 37 to direct its resources to the compartment in which the pathogen has previously been encountered 38 and would be the most likely source of infection. Importantly, this phenomenon provides a novel 39 means to therapeutically target innate immune effector cells to sites of specific disease localization 40 to potentially treat a wide spectrum of pathologies, including cancer, infection, and chronic 41 inflammatory disorders. 42 43 AUTHOR SUMMARY 44Vaccines that target adaptive immune memory have revolutionized medicine. This study 45 describes a novel strategy that works as a modified innate immune "vaccine" that exploits the 3 46 trained response of innate immune effector cells to clear pathology in a specific tissue site. 47Unlike memory of the adaptive immune system, which functions like a lock and key, innate 48 immune memory is more akin to a reflex response -like experienced muscle or neural cells that 49 are changed by a stimulus to respond more efficiently upon re-exposure. This change in behavior 50 through experience is the definition of learning. Our study suggests that this innate immune 51 learning occurs at different levels. Emergency hematopoiesis trains new innate immune cells in 52 the bone marrow to respond quickly and effectively to a non-specific threat; whereas, pathogen-53 specific training occurs at sites where cells making up the immunologic niche have had 54 interactions with a particular pathogen and have been trained to respond more robustly to it upon 55 re-presentation in the context of a danger signal. The speed with which new immune cells are 56 trained in the bone marrow in response to an imminent microbial threat and their subsequent 57 recruitment to the target organ site where that microbe typically resides suggests there are ways 58 the immune system communicates to coordinate this rapid response that are yet to be fully ...