Expansible residence decentralizes immune homeostasis

Abstract

Metazoans relegate specific tasks to dedicated organs that are established early in development, occupy discrete anatomic locations, and typically remain fixed in size. The adult immune system arises from a centralized hematopoietic niche that maintains self-renewing potential 1 , 2 , and upon maturation, becomes distributed throughout the body to monitor environmental perturbations, regulate tissue homeostasis, and mediate organism-wide defense. This study examines how immunity is integrated within adult mouse tissues while addressing issues of durability, expansibility, and contribution to organ cellularity. Focusing on antiviral T cell immunity, we observe durable maintenance of resident memory T cells (T RM ) 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. While resident memory indefinitely dominated most mucosal organs, surgical separation of parabiotic mice unexpectedly revealed a tissue-resident provenance for bloodborne effector memory T cells, and circulating memory slowly made substantial contributions to tissue immunity in some organs. Following additional microbial experiences via serial immunizations or pet shop mice co-housing, for most tissues we find tissue pliancy allows for the accretion of tissue-resident memory, without axiomatic erosion of preexisting antiviral T cell immunity. Extending these findings, we demonstrate tissue residence and organ pliancy are generalizable aspects underlying the homeostasis of innate and adaptive immunity. The immune system-at-large grows commensurate to microbial experience reaching up to 25% of visceral organ cellularity. Regardless of location, many white blood cell populations adopted a tissue residency program within nonlymphoid organs. Thus, residence, rather than renewal or recirculation, typifies nonlymphoid immune surveillance, and organs serve as a pliant storage reservoir that can accommodate the continuous expansion of the cellular immune system throughout life. While hematopoiesis (‘to make blood’) restores certain elements of the immune system, in parallel, nonlymphoid organs sustain an accrual of durable tissue-autonomous cellular immunity, resulting in the progressive decentralization of organismal immune homeostasis.

Tissue-Resident T Cells in Chronic Relapsing–Remitting Intestinal Disorders

“…Initially, T RM cells were considered to be strictly non-migrating T cell subsets-mostly based on short-term parabiosis experiments [52,130]. More recently, evidence was found for the developmental plasticity also of T RM cells as, upon restimulation, they may be able to enter the circulation and may affect systemic immunity in a most significant manner [104,106]. Intriguingly, during their non-resident stage, they still maintain a tropism for homing back to their site of origin [105].…”

“…As outlined above, T RM cells, at least under homeostatic conditions, do not generally recirculate and reside preferentially in nonlymphoid tissues, particularly at barrier sites, but occasionally also in lymph nodes and the spleen or local vascular compartments [103]. The most recent data obtained with Hobit fate mapping mice [104], skin transplant experiments [105] and with long-term parabionts [106] reveal a distinct view of the biology and the impact of T RM cells also for systemic immune responses. Immunosurveillance by CD8 + T RM cells is mostly ascribed to the rapid elimination of infected cells either via cytotoxic activity by producing cytotoxic granule-associated proteins such as granzymes and perforin or by directly, or indirectly, recruiting effector cells via chemokines or inflammatory cytokines [2,26].…”

“…During 30 days of parabiosis, donor and host cells were equilibrated in blood, and 200 days following their physical separation, a higher percentage of host cells than donor cells was found in the peripheral blood, indicating that they originated from cells that were not able to equilibrate during parabiosis, most likely cells within the tissues (T RM cells) that later rejoined the circulation ("ex-T RM " cells), giving rise to memory cells in blood (Figure 1). Collectively, it appears that T cells which adapted a T RM cell lifestyle within non-lymphoid organs, rather than circulating adaptive immune cells, represent the main cellular players for the maintenance of local immunosurveillance, while de novo haematopoiesis still contributes to systemic immunosurveillance, but becomes of decreasing relevance in this process of progressive decentralization of the maintenance at the level of the organism [106]. This shift in the relevance of primary versus secondary and tertiary lymphoid tissues with age is also reflected by the sharp decline in the thymic output of T cells after puberty [107].…”

Co-Ordination of Mucosal B Cell and CD8 T Cell Memory by Tissue-Resident CD4 Helper T Cells

“…The differentiation of T RM cells can occur independently of local antigen recognition in the peripheral tissue [ 22 , 23 , 24 ]; however, local antigenic re-stimulation of effector CD8 T cells in nonlymphoid tissue greatly enhances T RM formation [ 25 , 26 , 27 ]. Following the formation of T RM cells, it is believed that T RM maintenance is largely antigen or TCR signaling independent [ 28 ]. However, chronic low levels of TCR stimulation due to persistence of antigen following influenza virus infection or following immunization with an adenoviral vector facilitates the accumulation of a protective population of CD69 + CD8 T RM cells [ 29 , 30 ].…”

Therapeutic activation of virus-specific resident memory T cells within the glioblastoma microenvironment

“…One day after T cell transfer, we infected mice with pathogens of interest expressing the antigens ova or gp33; LCMV, Influenza A virus strain PR8 expressing gp33 (PR8gp33), or vesicular stomatitis virus (VSVova) intranasally, or VSVova intravenously (Figure 3). These infections result in the durable establishment of broadly distributed memory T cells, including TRM in the brain (17)(18)(19)(20)(21). Greater than 30 days post-infection (referred to as immune memory mice), we then established GBM tumors using an orthotopic model by intracranially implanting syngeneic GBM cell lines.…”