Papers by Tatiana Akimova
Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia–Reperfusion Injury
American Journal of Respiratory and Critical Care Medicine
RATIONALE Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to incre... more RATIONALE Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplantation. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. OBJECTIVES We hypothesized that T-regulatory (Treg) cells are able to dampen early ischemia/reperfusion events and thereby decrease risk of PGD, whereas that action is impaired in obese recipients. METHODS We evaluated Treg, T cells and inflammatory markers, plus clinical data, in 79 lung and 41 liver or kidney transplant recipients and studied two groups of mice on high fat diet (HFD), who developed ("inflammatory" HFD) or not ("healthy" HFD) low-grade inflammation with decreased Treg function. RESULTS We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Treg suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Treg from obese mice fail to control PGD, while IL-18 inhibition ameliorates lung inflammation. The IL-18 driven impairment in Treg suppressive function pre-transplant was associated with increased risk and severity of PGD in clinical lung transplant recipients. CONCLUSION Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Treg suppressive function along with IL-18 levels may serve as screening tools to identify pre-transplant obese recipients with increased risk of PGD.
Frontiers in Immunology
The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of mu... more The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of muscle cells, neurons and hematopoietic cells. By functioning in physiological feedback loops, Mef2 TFs promote the transcription of their repressor, Hdac9, thereby providing temporal control of Mef2-driven differentiation. Disruption of this feedback is associated with the development of various pathologic states, including cancer. Beside their direct involvement in oncogenesis, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg (eTreg) phenotype and for the activation of an epigenetic program that suppresses the anti-tumor immune responses of conventional T and B cells. We now report that as with Mef2d, the deletion of Mef2c in Tregs switches off the expression of Il10 and Icos and leads to enhanced antitumor immunity in syngeneic ...
Proceedings of the National Academy of Sciences, 2020
Significance To do the right thing at the right time, organisms need to glean cues from their env... more Significance To do the right thing at the right time, organisms need to glean cues from their environment. How they respond can then be described by reaction norms, i.e., by the relationship between the phenotype expressed (the phenology of an event) and the environment (the date when a given number of degree-days are achieved). We use information on 178 phenological events across the former Soviet Union. We found the timing of events to differ more between sites in spring and less in autumn. These patterns of local adaptation translate to a massive imprint on nature’s calendar: geographic variation in phenology is more pronounced in spring and less pronounced in autumn than if organisms were to respond equally everywhere.
Journal of Clinical Investigation, 2020
Cell Reports, 2020
Highlights d Lactate is metabolized by T cells and reduces NAD + to NADH d NAD + reduction to NAD... more Highlights d Lactate is metabolized by T cells and reduces NAD + to NADH d NAD + reduction to NADH impairs glycolytic flux via GAPDH d Lactate depletes post-GAPDH glycolytic intermediates and glucose-derived serine d Adding serine rescues T cell proliferation from lactateinduced reductive stress
Acta Carsologica, 2020
A comparison of karren formation on various rocks under diverse environmental conditions makes an... more A comparison of karren formation on various rocks under diverse environmental conditions makes an important contribution to our understanding of the formation and development of karst. In this regard, the present study brings a number of new insights through description of the karst development on marbles at the foothills of the Altai Mountains. We studied karst phenomena in the field and in the laboratory where structural-textural properties, mineral composition and quantity of carbonate components were determined. Rivers dissected karst surface and additionally uncovered carbonate rocks. The marble layers are faulted, folded and sheared, consequently containing numerous densely spaced net of discontinuities, which are often parallel. Brittle deformations significantly increased the rocks’ porosity, consequently making it more sensitive to water absorption and freezing thaw effect. Distinct continental climate, with extreme daily and seasonal temperature variations, conditions the ...
Cancers, 2020
Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvi... more Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvironment, including the actions of myeloid-derived suppressor cells (MDSCs). We investigated the role of the CCR2/MCP-1 pathway in MDSC-associated tumor progression in murine lung cancer models. Phenotypic profiling revealed maximal expression of CCR2 by tumor-resident MDSCs, and MCP-1 by transplanted TC1 tumor cells, respectively. Use of CCR2-knockout (CCR2-KO) mice showed dependence of tumor growth on CCR2 signaling. Tumors in CCR2-KO mice had fewer CCR2low MDSCs, CD4 T cells and Tregs than WT mice, and increased infiltration by CD8 T cells producing IFN-γ and granzyme-B. Effects were MDSC specific, since WT and CCR2-KO conventional T (Tcon) cells had comparable proliferation and production of inflammatory cytokines, and suppressive functions of WT and CCR2-KO Foxp3+ Treg cells were also similar. We used a thioglycolate-induced peritonitis model to demonstrate a role for CCR2/MCP-1 in t...
Cancers, 2019
Functions of the GCN5-related N-acetyltransferase (GNAT) family of histone/protein acetyltransfer... more Functions of the GCN5-related N-acetyltransferase (GNAT) family of histone/protein acetyltransferases (HATs) in Foxp3+ T-regulatory (Treg) cells are unexplored, despite the general importance of these enzymes in cell biology. We now show that two prototypical GNAT family members, GCN5 (general control nonrepressed-protein 5, lysine acetyltransferase (KAT)2a) and p300/CBP-associated factor (p300/CBP-associated factor (PCAF), Kat2b) contribute to Treg functions through partially distinct and partially overlapping mechanisms. Deletion of Gcn5 or PCAF did not affect Treg development or suppressive function in vitro, but did affect inducible Treg (iTreg) development, and in vivo, abrogated Treg-dependent allograft survival. Contrasting effects were seen upon targeting of each HAT in all T cells; mice lacking GCN5 showed prolonged allograft survival, suggesting this HAT might be a target for epigenetic therapy in allograft recipients, whereas transplants in mice lacking PCAF underwent acu...
Scientific Data, 2020
We present an extensive, large-scale, long-term and multitaxon database on phenological and clima... more We present an extensive, large-scale, long-term and multitaxon database on phenological and climatic variation, involving 506,186 observation dates acquired in 471 localities in Russian Federation, Ukraine, Uzbekistan, Belarus and Kyrgyzstan. The data cover the period 1890–2018, with 96% of the data being from 1960 onwards. The database is rich in plants, birds and climatic events, but also includes insects, amphibians, reptiles and fungi. The database includes multiple events per species, such as the onset days of leaf unfolding and leaf fall for plants, and the days for first spring and last autumn occurrences for birds. The data were acquired using standardized methods by permanent staff of national parks and nature reserves (87% of the data) and members of a phenological observation network (13% of the data). The database is valuable for exploring how species respond in their phenology to climate change. Large-scale analyses of spatial variation in phenological response can help...
Journal of Clinical Investigation, 2020
Scientific Reports, 2020
Foxp3+ T-regulatory (Treg) cells are capable of suppressing immune responses. Lysine acetylation ... more Foxp3+ T-regulatory (Treg) cells are capable of suppressing immune responses. Lysine acetylation is a key mechanism of post-translational control of various transcription factors, and when acetylated, Foxp3 is stabilized and transcriptionally active. Therefore, understanding the roles of various histone/protein deacetylases (HDAC) are key to promoting Treg-based immunotherapy. Several of the 11 classical HDAC enzymes are necessary for optimal Treg function while others are dispensable. We investigated the effect of HDAC10 in murine Tregs. HDAC10 deletion had no adverse effect on the health of mice, which retained normal CD4+ and CD8+ T cell function. However, HDAC10−/− Treg exhibited increased suppressive function in vitro and in vivo. C57BL/6 Rag1−/− mice adoptively transferred with HDAC10−/− but not wild Treg, were protected from developing colitis. HDAC10−/− but not wild-type mice receiving fully MHC-mismatched cardiac transplants became tolerant and showed long-term allograft su...
Abstract 1965: Inhibiting the CCR2/MCP-1 chemokine pathway blocks MDSC recruitment and promotes anti-tumor immunity
Tumor Biology, 2019
Вестник Пермского университета. Российская и зарубежная филология, 2018
Татьяна Ивановна Акимова д. филол. н., профессор кафедры русской и зарубежной литературы Мордовск... more Татьяна Ивановна Акимова д. филол. н., профессор кафедры русской и зарубежной литературы Мордовский государственный университет им. Н. П. Огарева 430005, Россия, г. Саранск, ул. Большевистская,
Journal of Clinical and Translational Science, 2019
OBJECTIVES/SPECIFIC AIMS: Objective: apply checkpoint inhibitors that are specific to the exhaust... more OBJECTIVES/SPECIFIC AIMS: Objective: apply checkpoint inhibitors that are specific to the exhaustive markers expressed on tumor CD8+ T-cells ex vivo in order to improve cytokine release and cytotoxic function in comparison to two control groups: (1.) T-cells that receive no antibodies; (2.) T-cells that receive standard inhibition with PD-1 and CTLA-4 antibodies only. Long-term objective: provide personalized medicine in the treatment of HCC by using checkpoint inhibitors that are specific to the receptors expressed by an individual tumor. METHODS/STUDY POPULATION: The study population includes patients undergoing liver transplantation or surgical resection for HCC. Two grams of tumor, two grams of healthy liver tissue at least one centimeter from the tumor margin, and 50 milliliters of blood will be obtained. Solid tissue will be mechanically and enzymatically disrupted and CD8+ T-cells will be isolated from all sites. Using flow cytometry, the expression of surface receptors PD-1,...
The Journal of Heart and Lung Transplantation, 2019
Return to work (RTW) and social participation after chronic illness improves functional outcomes,... more Return to work (RTW) and social participation after chronic illness improves functional outcomes, social integration and quality of life, enabling positive contribution to society. Despite this, many studies around the world have reported RTW rates as low as 28% in lung transplant recipients. This study aims to evaluate the number of patients that RTW, predictors of RTW and social participation in Australian lung transplant recipients Methods: In a cross-sectional sample of lung transplant recipients, we assessed self-reported pre and post-transplant employment, social participation including volunteer work and carer/social engagement. Quality of life measurements including self-reported hospital admissions, sick days and Euroquol 5D-5L scores were collated. Results: 82 patients (47 males; mean age 57.8 §14.5) are included to date. Underlying condition requiring transplantation included COPD (42%), Cystic fibrosis (23%), ILD (20%) and other (15%). Mean time post-transplant at time of survey was 5 years. At the time of transplant: 15% (n=12) were working, 11% (n=9) were looking after a child, 10% (n=9) had retired, 10% (n=8) were carers for family members with disability or chronic illness, 7% (n=6) were engaged in voluntary work, 6% (n=5) of patients had never worked and 2% (n=2) were studying. The majority of patients (79%) had worked at some-point. Following transplant: 40% (n=32) are retired, 27% (n= 22) have returned to work, 7% (n=6) looking after children, 6% (n=5) engaged in voluntary work, 4% (n=3) are studying and 4% (n=3) are carers for family members with disability or chronic illness. The mean Euroquol health status scores (scale 0 to 100 [best health possible]) for the post-transplant population were: 86 (carer/volunteer/ studying), 82 (working), 80 (retired) and 77 (not working). Conclusion: This study provides preliminary data in Australia comparable to worldwide studies, with an estimated RTW rate of 27% post-lung transplantation. However, patients are also engaged in other activities including volunteer work and carer responsibilities, which has not been previously documented. Further analysis is planned. Return to work and social engagement should be encouraged for lung transplant recipients for improving health status.
Science Translational Medicine, 2019
PD-L1 + tumor cells, but not macrophages, are likely responsible for inhibiting tumor-specific T ... more PD-L1 + tumor cells, but not macrophages, are likely responsible for inhibiting tumor-specific T cells in early-stage human lung tumors.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2018
T-regulatory (Treg) cells are like other cells present throughout the body in being subject to bi... more T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 13, 2018
Alterations in gut microbiota are known to affect intestinal inflammation and obesity. Antibiotic... more Alterations in gut microbiota are known to affect intestinal inflammation and obesity. Antibiotic treatment can affect weight gain by elimination of histone deacetylase (HDAC) inhibitor-producing microbes, which are anti-inflammatory by augmenting regulatory T (T) cells. We asked whether mice that lack HDAC6 and have potent suppressive T cells are protected from microbiota-induced accelerated weight gain. We crossed wild-type and HDAC6-deficient mice and subjected the offspring to perinatal penicillin, inducing weight gain via microbiota disturbance. We observed that male HDAC6-deficient mice were not protected and developed profoundly accelerated weight gain. The antibiotic-exposed HDAC6-deficient mice showed a mixed immune phenotype with increased CD4 and CD8 T-cell activation yet maintained the enhanced T cell-suppressive function phenotype characteristic of HDAC6-deficient mice. 16S rRNA sequencing of mouse fecal samples reveals that their microbiota diverged with time, with HDA...
Expert opinion on therapeutic targets, Jan 10, 2018
Scientific reports, Jan 16, 2018
We report that human conventional CD15neutrophils can be isolated in the peripheral blood mononuc... more We report that human conventional CD15neutrophils can be isolated in the peripheral blood mononuclear cell (PBMC) layer during Ficoll gradient separation, and that they can impair T cell proliferation in vitro without concomitant neutrophil activation and killing. This effect was observed in a total of 92 patients with organ transplants, lung cancer or anxiety/depression, and in 18 healthy donors. Although such features are typically associated in the literature with the presence of certain myeloid-derived suppressor cell (PMN-MDSC) populations, we found that commercial centrifuge tubes that contained membranes or gels for PBMC isolation led to up to 70% PBMC contamination by CD15neutrophils, with subsequent suppressive effects in certain cellular assays. In particular, the suppressive activity of human MDSC should not be evaluated using lectin or microbead stimulation, whereas assays involving soluble or plate-bound antibodies or MLR are unaffected. We conclude that CD15neutrophil ...
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Papers by Tatiana Akimova