Biology subjects

Victorino, F.

Publications and source records attributed to Victorino, F..

4 recordsLinked to original sources

bioRxiv2021

NK cell metabolic adaptation to infection promotes survival and viral clearance.

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1 (HIF-1) is a feature of NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1 KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF1-deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF1-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

immunology↗

bioRxiv2020

Chemokine Signatures Of Pathogen-Specific T Cells I: Effector T Cells

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 varied 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. Here, using different in vivo 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 role of T cell-produced chemokines in infectious and other diseases.

immunology↗

bioRxiv2018

Aging Boosts Antiviral CD8+T Cell Memory Through Improved Engagement Of Diversified Recall Response Determinants

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 naive CD8+T cells in the first place. Thus, our findings are consistent with the recently proposed \"rebound model\" that stipulates a gradual alignment of naive and CD8+TM properties, and identify a diversified collection of potential targets that may be exploited for the therapeutic modulation of CD8+TM immunity.

immunology↗

bioRxiv2017

Aging Of Antiviral CD8+ Memory T Cells Fosters Increased Survival, Metabolic Adaptations And Lymphoid Tissue Homing

Aging of established antiviral T cell memory fosters 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 (CD8+TM) homeostasis. Over time, CD8+TM become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+TM quiescence and fitness but also impart the re-acquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+TM 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+TM poised for greater recall responses.\n\nABBREVIATIONST cell subsets

immunology↗