T CELL MEMORY Efficient at Migrating to Inflamed Peripheral Tissues

RESEARCH HIGHLIGHTS T CELL MEMORY efficient at migrating to inflamed peripheral tissues. These data suggest that tissue-resident memory CD8+ T cells markedly outnumber those New insight on old-timers that are recirculating and that our current paradigms of memory T cell Memory T cells ensure that the recirculate between the blood and subsets require revision. immune response is more effective non-lymphoid tissues and respond Cui et al. explored how metabolic against re-infecting pathogens. Two rapidly to re-infecting pathogens. processes regulate longevity in mem- key distinctions between memory A further set of tissue-resident memory CD8+ T cells. They compared + CD8 T cells and their naive counter- ory T (TRM) cells have been described gene expression profiles of naive, parts are crucial for this: first, mem- that are retained in non-lymphoid effector and memory CD8+ T cells ory T cells have distinct migratory tissues and do not recirculate. The and found that the glycerol channel patterns; and second, they survive for relative contribution of each subset to aquaporin 9 (AQP9) was selectively longer. New studies by Steinert et al. immune memory has been unclear; expressed by memory CD8+ T cells. and Cui et al. offer fresh insight into to address this, Steinert et al. devel- These cells were shown to upregulate both of these aspects of memory. oped a quantitative immunofluores- AQP9 in response to stimulation Memory CD8+ T cells have been cence microscopy (QIM) method. with interleukin‑7 (IL‑7) — and, to a divided into distinct subsets on the our current In a mouse model of lymphocytic lesser extent, in response to IL‑15 — basis of putative trafficking and func- paradigms choriomeningitis virus (LCMV) and deficiency of AQP9 impaired the tional properties. Central memory T infection, standard protocols for cell survival of memory but not effector of memory + (TCM) cells are suggested to be long- isolation markedly underestimated CD8 T cells during LCMV infection. lived memory cells that recirculate T cell subsets the frequencies of LCMV-specific Further experiments suggested via secondary lymphoid organs require revision memory CD8+ T cells in tissues, that AQP9 deficiency impairs (SLOs), whereas effector memory T particularly in non-lymphoid sites, memory CD8+ T cell survival by (TEM) cells are thought to primarily when compared with QIM. Indeed, preventing glycerol uptake, which QIM analyses suggested that more is required for the synthesis of memory CD8+ T cells are found in triglycerides. Triglycerides serve the blood and peripheral tissues as a source of fatty acids for fatty than in SLOs. acid oxidation, a metabolic process Parabiosis experiments showed that generates energy for memory that most memory CD8+ T cells in T cell survival. Consistent with this, peripheral tissues do not recirculate. AQP9‑deficient memory CD8+ T cells This suggests that the majority had reduced ATP levels, and the of memory CD8+ T cells in non- overexpression of genes involved in lymphoid tissues are TRM cells, rather triglyceride synthesis prolonged their than TEM cells, although bona fide survival. Additional analyses showed TEM cells could be detected exiting that IL‑7 also increases the expression tissues via lymphatics. CD69 expres- of genes involved in triglyceride sion is often used to define TRM cells, synthesis in previously activated but but the authors found that a sub- not naive CD8+ T cells. Therefore, stantial number of resident memory IL‑7 promotes memory CD8+ T cell CD8+ T cells do not express this survival not only through the induc- marker. Furthermore, many of the tion of anti-apoptotic genes but memory CD8+ T cells that entered also by supporting their metabolic peripheral tissues (a migratory activities. behaviour associated with TRM cells Yvonne Bordon or TEM cells) expressed the lymph ORIGINAL RESEARCH PAPERS Steinert, E. M. et al. node-homing molecule CD62L, Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell which is typically used to define 161, 737–749 (2015) | Cui, G. et al. IL‑7‑induced TCM cells. In fact, adoptive transfer glycerol transport and TAG synthesis promotes experiments showed that purified memory CD8+ T cell longevity. Cell 161, 750–761 Creative Images/Alamy Creative (2015) TCM cells and TEM cells were equally NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | JUNE 2015 © 2015 Macmillan Publishers Limited. All rights reserved.

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