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Tissue-resident effector memory T cells respond rapidly after reencountering antigen. Masopust and colleagues show that memory CD8⁺ T cells also induce the release of chemokines, then recruit more memory cells to the site of infection.

Tissue-resident memory (T_RM) cells are generally stably maintained in discrete tissues or organs. Masopust and colleagues show that T_RM cells can reenter the circulation, and exhibit considerable plasticity, although they retain a proclivity to reestablish themselves in their tissue of origin.

Masopust and colleagues show that mucosal tissue-resident memory T cells proliferate in situ in response to local antigen and dominate the local recall response.

An HIV vaccine that elicits both antibodies and cellular immune responses confers long-lasting protection against viral challenge in nonhuman primates.

A γδ T cell–IL-3 signalling axis is defined that controls the allergen responsiveness of cutaneous sensory neurons, leading to evidence for an immune rheostat that governs sensory neuronal responses to allergens on first exposure.

In this Review, Künzli and Masopust provide updates on our understanding of the biology of memory CD4⁺ T cells as well as key technological advances that facilitate their characterization.

Through iterative cycles of viral challenge and rechallenge over ten years, mouse T cells are demonstrated to have essentially infinite potential for population expansion and longevity without malignant transformation or loss of functional competence.

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.

Notch signaling promotes the maintenance of lung-resident CD8⁺ memory T cells that are transcriptionally poised for rapid effector responses but have heightened expression of inhibitory receptors, suggestive of tight regulation.

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.

The immunosuppressive tumor environment and the lack of functional anti-tumor immunity are major limiting factors in immunotherapy. Here the authors show that human and mouse tumors are infiltrated by virus-specific memory T cells, which can be harnessed by viral peptides to induce local and systemic anti-tumor immunity and synergize with checkpoint blockade.

Here, the authors describe how T cell trafficking to distinct tissues is regulated under inflammatory and non-inflammatory conditions. They explain how the unique migratory properties of different T cell populations are intimately connected to their functions and, furthermore, discuss whether the ever-expanding nomenclature for T cell subsets is a help or a hindrance to immunologists.

Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.

Repeated exposure to pathogens and generation of T-cell memory is thought to result in attrition of the pre-existing memory T cell pool to maintain the overall size of the memory compartment constant. This work shows that new effector memory cells can be generated in large numbers without greatly impacting pre-existing memory.

There is emerging evidence that mice with a history of microbial exposures can better model the human immune system than laboratory mice maintained in pathogen-free conditions. In this Perspective, Rehermann and colleagues summarize different approaches that have been used to incorporate microbiota and pathogen exposures into laboratory mouse models. They suggest that the term ‘mice with natural microbiota’ should be used instead of ‘dirty mice’ to describe these systems in the future.

Using an iterative boost and transplantation model to generate multilifetime T cells, Mi et al. show that cellular epigenetic age can be uncoupled from organism age. While naive T cells appear epigenetically young, memory T cells and T-ALL leukemia can exhibit epigenetic ages exceeding the organismal lifespan.

The function of B cells in peripheral blood and secondary lymphoid organs has long been appreciated but whether and how they contribute to tissue immune homeostasis is lesser known. Non-lymphoid organs harbour tissue-resident B cells that include a substantial population of B-1 cells and promote homeostatic anti-inflammatory macrophage polarization via IL-10, with profound effects on bacterial clearance during local infection.

Buggert and colleagues provide a broad picture in this review of circulating and tissue-resident memory CD8⁺ T cells, which are ultimately responsible for effective immune surveillance.

Two papers published recently in Science exploit new transgenic mouse systems to explore the path that activated CD8⁺ T cells take on the way to memory differentiation.

The cytokine TGF-β maintains the residency of cells of the immune system in barrier tissues. Kaplan and colleagues demonstrate that specific integrins expressed by epithelial cells activate latent TGF-β and that this is critical to maintain residency of cells of the immune system in the skin and gut.

The immune system of laboratory mice raised in an ultra-hygienic environment resembles that ofnewborn humans, but can be induced to resemble the immune system of adult humans or 'dirty' mice by co-housing with pet store-bought mice.

Jameson and colleagues show that the establishment of resident memory CD8⁺ T cells in nonlymphoid tissues requires transcriptional downregulation of the trafficking molecule S1P₁, mediated by induced loss of the transcription factor KLF2.

Activation of P2RX7 receptors by extracellular ATP is required for the generation, maintenance and function of central and tissue-resident CD8⁺ memory T cells.

CD8⁺ tissue resident memory T cells (T_RM cells) are essential for defence against pathogens and malignancies. Prior work had indicated that these cells form within inflamed tissue, but there is emerging evidence that a pool of T_RM cell precursors exists within the circulation. This Review examines the processes and signals within the lymphoid compartment that determine lineage decisions towards the formation of T_RM cells.

A transplantable mouse model of persistent cutaneous melanoma shows that immune-mediated tumour suppression can result in a state of melanoma–immune equilibrium, and that tissue-resident memory T cells are essential drivers of this equilibrium state.

The consumption of exogenous free fatty acids by tissue-resident memory T (T_rm) cells is critical for their long-term survival and antiviral function, and appears to be a conserved feature of T_rm cells in both mouse and man, a recent paper published in Nature demonstrates.