Quantifying The Durability, Expansibility, And Tissue-Autonomous Nature Of The Immune System Uncovers A Resident Reservoir For Circulating Immunity

Abstract Immune cells develop in specialized lymphoid organs, but the mature immune system is integrated throughout the body and regulates tissue homeostasis and defense. This study examines how immunity persists within adult murine tissues while addressing issues of tissue autonomy, resistance to perturbations, and numerical contribution to the cellularity of visceral organs. Using quantitative immunofluorescent microscopy, we report that the immune system is expansible in nonlymphoid tissues following microbial experience, and hematopoietic cells comprise up to 30% of cells in visceral organs of laboratory mice housed in non-SPF conditions. Most hematopoietic cells in nonlymphoid tissues were autonomously maintained for >30 days, without contribution from circulation or primary lymphoid organs. Focusing on antiviral T cell immunity, we demonstrate tissue-autonomous maintenance of resident memory T cells for >200 days. Resident T cell memory was largely durable following significant environmental perturbations and de novo immune responses. Once established, resident T cells did not require the T cell receptor for survival, longevity, or retention of a poised effector-like phenotype. Ultimately, T cell memory did decay in some organs, not others, and gradually increased in circulation. Surgical separation of parabiotic mice unexpectedly revealed a tissue-resident provenance for memory T cells in peripheral blood. We propose a model whereby circulating memory T cells do not replenish resident populations, but instead a tissue-resident reservoir supports long-term maintenance of the bloodborne pool. Collectively, these data demonstrate the durability and autonomous nature of the tissue-integrated immune system.