How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial ...infections and that these increased acetate concentrations are required for optimal memory CD8+ T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8+ T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8+ T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8+ T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8+ T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.
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•Serum acetate levels rapidly increase following systemic bacterial infection•Memory CD8+ T cells take up acetate and expand their acetyl-CoA pool•Increased acetyl-CoA levels catalyze functional activity of GAPDH by acetylation•Augmented glycolytic flux rates boost rapid recall responses of memory CD8+ T cells
How systemic metabolic alterations during acute infections impact immune-cell function remains poorly understood. Hess and colleagues demonstrate that acetate rapidly increases during infections, which drives acetylation of GAPDH in memory CD8+ T cells and thereby catalyzes the rapid recall response.
(
) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have ...proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the
antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional
-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung
burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon
challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded
antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.
The envelope of human cytomegalovirus (HCMV) consists of a large number of glycoproteins. The most abundant glycoprotein in the HCMV envelope is the glycoprotein M (UL100), which together with ...glycoprotein N (UL73) form the gM/gN protein complex. Using yeast two-hybrid screening, we found that the gM carboxy-terminal cytoplasmic tail (gM-CT) interacts with FIP4, a Rab11-GTPase effector protein. Depletion of FIP4 expression in HCMV-infected cells resulted in a decrease in infectious virus production that was also associated with an alteration of the HCMV assembly compartment (AC) phenotype. A similar phenotype was also observed in HCMV-infected cells that expressed dominant negative Rab11(S25N). Recently, it has been shown that FIP4 interactions with Rab11 and additionally with Arf6/Arf5 are important for the vesicular transport of proteins in the endosomal recycling compartment (ERC) and during cytokinesis. Surprisingly, FIP4 interaction with gM-CT limited binding of FIP4 with Arf5/Arf6; however, FIP4 interaction with gM-CT did not prevent recruitment of Rab11 into the ternary complex. These data argued for a contribution of the ERC during cytoplasmic envelopment of HCMV and showed a novel FIP4 function independent of Arf5 or Arf6 activity.
Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde ...virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control.
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Engineered arenaviruses induce potent tumor self-specific CD8 T cell (CTL) responseCombinations of distantly but not closely related arenavirus vectors eliminate tumorsVector backbone-targeted CTL responses compete against tumor self-reactive CTLsOptimized vector combinations reshuffle immunodominance to break self-tolerance
Therapeutic tumor vaccination should break self-tolerance. Assessing combinations of engineered arenavirus vectors, Bonilla et al. find that distantly related vector combinations reshuffle T cell immunodominance hierarchies to break self-tolerance and eliminate established solid tumors, whereas closely related vectors interfere because of immunodominance of anti-vector CD8 T cells rather than antibodies.
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