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In metazoans, specific tasks are relegated to dedicated organs that are established early in development, occupy discrete locations and typically remain fixed in size. The adult immune system arises from a centralized haematopoietic niche that maintains self-renewing potential1,2, and—upon maturation—becomes distributed throughout the body to monitor environmental perturbations, regulate tissue homeostasis and mediate organism-wide defence. Here we examine how immunity is integrated within adult mouse tissues, and address issues of durability, expansibility and contributions to organ cellularity. Focusing on antiviral T cell immunity, we observed durable maintenance of resident memory T cells up to 450 days after infection. Once established, resident T cells did not require the T cell receptor for survival or retention of a poised, effector-like state. Although resident memory indefinitely dominated most mucosal organs, surgical separation of parabiotic mice revealed a tissue-resident provenance for blood-borne effector memory T cells, and circulating memory slowly made substantial contributions to tissue immunity in some organs. After serial immunizations or cohousing with pet-shop mice, we found that in most tissues, tissue pliancy (the capacity of tissues to vary their proportion of immune cells) enables the accretion of tissue-resident memory, without axiomatic erosion of pre-existing antiviral T cell immunity. Extending these findings, we demonstrate that tissue residence and organ pliancy are generalizable aspects that underlie homeostasis of innate and adaptive immunity. The immune system grows commensurate with microbial experience, reaching up to 25% of visceral organ cellularity. Regardless of the location, many populations of white blood cells adopted a tissue-residency program within nonlymphoid organs. Thus, residence—rather than renewal or recirculation—typifies nonlymphoid immune surveillance, and organs serve as pliant storage reservoirs that can accommodate continuous expansion of the cellular immune system throughout life. Although haematopoiesis restores some elements of the immune system, nonlymphoid organs sustain an accrual of durable tissue-autonomous cellular immunity that results in progressive decentralization of organismal immune homeostasis. Investigations in mice using parabiosis and cohousing experiments reveal that nonlymphoid organs serve as reservoirs of tissue-autonomous cellular immunity, leading to the decentralization of organism-level immune homeostasis.

Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

Memory CD8 T cells, generated by natural pathogen exposure or intentional vaccination, protect the host against specific viral infections. It has long been proposed that the number of memory CD8 T cells in the host is inflexible, and that individual cells are constantly competing for limited space. Consequently, vaccines that introduce over-abundant quantities of memory CD8 T cells specific for an agent of interest could have catastrophic consequences for the host by displacing memory CD8 T cells specific for all previous infections. To test this paradigm, we developed a vaccination regimen in mice that introduced as many new long-lived memory CD8 T cells specific for a single vaccine antigen as there were memory CD8 T cells in the host before vaccination. Here we show that, in contrast to expectations, the size of the memory CD8 T-cell compartment doubled to accommodate these new cells, a change due solely to the addition of effector memory CD8 T cells. This increase did not affect the number of CD4 T cells, B cells or naive CD8 T cells, and pre-existing memory CD8 T cells specific for a previously encountered infection were largely preserved. Thus, the number of effector memory CD8 T cells in the mammalian host adapts according to immunological experience. Developing vaccines that abundantly introduce new memory CD8 T cells should not necessarily ablate pre-existing immunity to other infections.

Our immune system usually ignores 'friendly' gut bacteria. But when infection with a pathogen damages the intestine's mucosal lining, the resident microbes can invade the body, inducing immune responses directed at themselves.

Replying to: R. M. Welsh and L. K. Selin , 10.1038/nature08091 (2009) We reported that it is possible to increase the total number of memory CD8 T cells within an organism, and to establish preternatural numbers of vaccine-specific effector memory CD8 T cells while preserving naive CD8 T cells and most pre-existing memory CD8 T cells specific for a previously encountered infection https://www.nature.com/articles/nature08091 1. These findings raise new questions regarding the regulation and limits of generating CD8 T cell immunity. Our discussion highlighted three points related to the issue of attrition. First, that it is possible to over-estimate perceived attrition by only examining percentages (see Fig. 1 of ref. 1)2. Second, our vaccine regimen resulted predominantly in the generation of effector memory CD8 T cells located outside of lymph nodes. It remains possible that the number of lymph node central memory T cells remains tightly regulated. Third, we noted that our data did not refute that attrition could happen under a variety of circumstances. However, our data demonstrate that attrition is not an axiomatic property of immunization, mandated by stringent regulation of the size of the total memory CD8 T-cell compartment. Indeed, we saw no evidence of attrition after single infections with a virus (vaccinia), an intracellular bacteria (Listeria monocytogenes) and a parasite that induces massive splenomegaly (Plasmodium yoelii), and observed comparatively little attrition after a heterologous prime–boost regimen involving successive immunization with three viruses1.