New insight on old-timers

Abstract

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