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Pathogen-specific memory T cells (T M ) contribute to enhanced immune protection under conditions of reinfection, and their effective recruitment into a recall response relies, in part, on cues imparted by chemokines that coordinate their spatiotemporal positioning. An integrated perspective, however, needs to consider T M as a potentially relevant chemokine source themselves. In this study, we employed a comprehensive transcriptional/translational profiling strategy to delineate the identities, expression patterns, and dynamic regulation of chemokines produced by murine pathogen-specific T M CD8 + T M , and to a lesser extent CD4 + T M , are a prodigious source for six select chemokines (CCL1/3/4/5, CCL9/10, and XCL1) that collectively constitute a prominent and largely invariant signature across acute and chronic infections. Notably, constitutive CCL5 expression by CD8 + T M serves as a unique functional imprint of prior antigenic experience; induced CCL1 production identifies highly polyfunctional CD8 + and CD4 + T M subsets; long-term CD8 + T M maintenance is associated with a pronounced increase of XCL1 production capacity; chemokines dominate the earliest stages of the CD8 + T M recall response because of expeditious synthesis/secretion kinetics (CCL3/4/5) and low activation thresholds (CCL1/3/4/5/XCL1); and T M chemokine profiles modulated by persisting viral Ags exhibit both discrete functional deficits and a notable surplus. Nevertheless, recall responses and partial virus control in chronic infection appear little affected by the absence of major T M chemokines. Although specific contributions of T M -derived chemokines to enhanced immune protection therefore remain to be elucidated in other experimental scenarios, the ready visualization of T M chemokine-expression patterns permits a detailed stratification of T M functionalities that may be correlated with differentiation status, protective capacities, and potential fates., (Copyright © 2020 by The American Association of Immunologists, Inc.)

The determinants of protective CD8+ memory T cell (CD8+TM) immunity remain incompletely defined and may in fact constitute an evolving agency as aging CD8+TM progressively acquire enhanced rather than impaired recall capacities. Here, we show that old as compared to young antiviral CD8+TM more effectively harness disparate molecular processes (cytokine signaling, trafficking, effector functions, and co-stimulation/inhibition) that in concert confer greater secondary reactivity. The relative reliance on these pathways is contingent on the nature of the secondary challenge (greater for chronic than acute viral infections) and over time, aging CD8+TM re-establish a dependence on the same accessory signals required for effective priming of naïve CD8+T cells in the first place. Thus, our findings reveal a temporal regulation of complementary recall response determinants that is consistent with the recently proposed "rebound model" according to which aging CD8+TM properties are gradually aligned with those of naïve CD8+T cells; our identification of a broadly diversified collection of immunomodulatory targets may further provide a foundation for the potential therapeutic "tuning" of CD8+TM immunity., Competing Interests: The authors have declared that no competing interests exist.

Aging of established antiviral T cell memory can foster a series of progressive adaptations that paradoxically improve rather than compromise protective CD8 + T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8 + memory T cell (T M ) homeostasis. Over time, CD8 + T M generated in the wake of an acute infection with the natural murine pathogen lymphocytic choriomeningitis virus become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8 + T M quiescence and fitness but also impart the reacquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8 + T M from blood and nonlymphoid tissues to lymphatic organs results in CD8 + T M accumulations in bone marrow, splenic white pulp, and, particularly, lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8 + T M poised for greater recall responses., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Rapid activation and proliferative expansion of specific CD8(+) memory T (CD8(+) TM ) cells upon antigen re-encounter is a critical component of the adaptive immune response that confers enhanced immune protection. In this context, however, the requirements for costimulation in general, and CD28 signaling in particular, remain incompletely defined. In the current issue of the European Journal of Immunology, Fröhlich et al. [Eur. J. Immunol. 2016. 46: 1644-1655] provide definitive evidence that optimal elaboration of CD8(+) TM -cell recall responses is indeed contingent on CD28 expressed by these cells. Here, we discuss the "CD28 costimulation paradigm" in its historical context and highlight some of the unresolved complexities pertaining to CD28-dependent interactions that shape CD8(+) T-cell phenotypes, functionalities, and recall reactivity., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)