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The choreography of complex immune responses, including the priming, differentiation, and modulation of specific effector T cell populations generated in the immediate wake of an acute pathogen challenge, is in part controlled by chemokines, a large family of mostly secreted molecules involved in chemotaxis and other patho/physiological processes. T cells are both responsive to various chemokine cues and a relevant source for certain chemokines themselves; yet, the actual range, regulation, and role of effector T cell-derived chemokines remains incompletely understood. In this study, using different in vivo mouse models of viral and bacterial infection as well as protective vaccination, we have defined the entire spectrum of chemokines produced by pathogen-specific CD8 + and CD4 + T effector cells and delineated several unique properties pertaining to the temporospatial organization of chemokine expression patterns, synthesis and secretion kinetics, and cooperative regulation. Collectively, our results position the "T cell chemokine response" as a notably prominent, largely invariant, yet distinctive force at the forefront of pathogen-specific effector T cell activities and establish novel practical and conceptual approaches that may serve as a foundation for future investigations into the role of T cell-produced chemokines in infectious and other diseases., (Copyright © 2020 by The American Association of Immunologists, Inc.)

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.)

Background: Immunosuppression has been recognized as a major cause of sepsis-related mortality. Currently, there is much interest in identifying central hubs controlling septic immunoparalysis. In this context, in this study, the authors investigate the role of microRNA-31 (miR-31) as a regulator of T cell functions., Methods: Primary human T cells were separated from healthy volunteers (n = 16) and from sepsis patients by magnetic beads (n = 23). Expression of mRNA/microRNA (miRNA) was determined by real-time polymerase chain reaction. Gene silencing was performed by small interfering RNA transfection, and miRNA-binding sites were validated by reporter gene assays. Effects of miR-31 or anti-miR-31 transfection were analyzed by real-time polymerase chain reaction, Western blotting, and flow cytometry., Results: Overexpression of miR-31 in stimulated CD4 T cells promoted a proinflammatory phenotype with increased levels of interferon-γ (1.63 ± 0.43; P = 0.001; means ± SD) and reduced expression of interleukin (IL)-2 (0.66 ± 0.19; P = 0.005) and IL-4 (0.80 ± 0.2; P = 0.0001). In contrast, transfection of anti-miR-31 directed cells toward a TH2 phenotype. Effects on IL-2 and IL-4 were mediated by targeting of nuclear factor-kappa B-inducing kinase and factor-inhibiting hypoxia-inducible factor-1α. Interferon-γ, however, was influenced via control of signaling lymphocytic activation molecule (SLAM)-associated protein, an essential adaptor molecule of immunomodulatory SLAM receptor signaling, which was identified as a novel target gene of miR-31. In sepsis patients, an epigenetically driven down-regulation of miR-31 was found (0.44 ± 0.25; P = 0.0001), associated with increased nuclear factor-kappa B-inducing kinase, factor-inhibiting hypoxia-inducible factor-1α, SLAM-associated protein expression, and a cytokine shift toward TH2., Conclusions: In this study, the authors provide novel evidence of miR-31 as an emerging key posttranscriptional regulator of sepsis-associated immunosuppression. The study results contribute to a further understanding of septic immunoparalysis and provide new perspectives on miRNA-based diagnostic approaches.