scholarly journals A Multi-Scale Model for the Spread of HIV in a Population Considering the Immune Status of People

Processes ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1924
Author(s):  
Sol de Amor Vásquez-Quintero ◽  
Hernán Darío Toro-Zapata ◽  
Dennis Alexánder Prieto-Medellín
Keyword(s):  
T Cells ◽  
Immune System ◽  
Cd4 T Cells ◽  
Population Level ◽  
Scale Model ◽  
Future Research ◽  
Specific Cell ◽  
Multi Scale ◽  
Number Of Sexual Partners ◽  
Population Scale

A multi-scale mathematical model is proposed, seeking to describe the propagation of Human Immunodeficiency Virus (HIV) in a group of young people between 15 and 24 years of age, through unprotected sexual contact. The uses of antiretroviral therapy (ART) and therapeutic failure are considered to show how the rate of propagation and prevalence are affected. The model consists of a complex network modeling the interactions on the population scale, coupled with the immunological dynamics of each individual, which is modeled by a system of differential equations. The immunological model allows to observe some known facts from the literature, such as to control HIV infection in the immune system, it is necessary to reduce the probability of healthy CD4 T cells becoming infected or increase the probability at which cells of the specific cell response against HIV eliminate infected CD4 T cells. At the population level, it is shown that, to have a high prevalence, it is not necessary for the virus to spread rapidly at the beginning of the simulation time. Additionally, it is observed that a greater number of sexual partners induces higher HIV prevalence. Using ART in the immune system reduces the number of infected CD4 T cells and, consequently, helps to reduce the spread of infection at the population scale. An important result observed in simulations is that the average number of HIV carriers who abandon ART is greater than those who access it. The study adds to the available literature an original simulation model that describes the dynamics of HIV propagation in a population, considering the immune state of people within that population, and serves as a basis for future research involving more detailed aspects aiming for a model closest to reality.

scholarly journals Multi-Approach and Multi-Scale Model of CD4+ T Cells Predicts Switch-Like and Oscillatory Emergent Behaviors in Inflammatory Response to Infection

2020 ◽  
Author(s):  
Kenneth Y. Wertheim ◽  
Bhanwar Lal Puniya ◽  
Alyssa La Fleur ◽  
Ab Rauf Shah ◽  
Matteo Barberis ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Multiple Scales ◽  
Spatial Scales ◽  
The Body ◽  
Scale Model ◽  
Human Immune System ◽  
Multi Scale ◽  
Computational Performance ◽  
Emergent Behaviors

Immune responses rely on a complex adaptive system in which the body and infections interact at multiple scales and in different compartments. We developed a modular model of CD4+ T cells which uses four modeling approaches to integrate processes taking place at three spatial scales in different tissues. In each cell, signal transduction and gene regulation are described by a logical model, metabolism by constraint-based models. Cell population dynamics are described by an agent-based model and systemic cytokine concentrations by ordinary differential equations. A Monte Carlo simulation algorithm allows information to flow efficiently between the four modules by separating the time scales. Such modularity improves computational performance and versatility, and facilitates data integration. Our technology helps capture emergent behaviors that arise from nonlinear dynamics interwoven across three scales. Multi-scale insights added to single-scale studies allowed us to identify switch-like and oscillatory behaviors of CD4+ T cells at the population level, which are both novel and immunologically important. We envision our model and the generic framework encompassing it to become the foundation of a more comprehensive model of the human immune system.

scholarly journals Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 813
Author(s):  
Norwin Kubick ◽  
Pavel Klimovich ◽  
Patrick Henckell Flournoy ◽  
Irmina Bieńkowska ◽  
Marzena Łazarczyk ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Positive Selection ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Single Gene ◽  
Ancestral Reconstruction ◽  
Critical Function ◽  
Interleukin Receptors

Understanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells’ presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their origin. We traced the evolution of interleukins and their receptors from Placozoa to primates. We performed phylogenetic analysis, ancestral reconstruction, HH search, and positive selection analysis. Our results indicated that various interleukins' emergence predated CD4+ T cells divergence. IL14 was the most ancient interleukin with homologs in fungi. Invertebrates also expressed various interleukins such as IL41 and IL16. Several interleukin receptors also appeared before CD4+ T cells divergence. Interestingly IL17RA and IL17RD, which are known to play a fundamental role in Th17 CD4+ T cells first appeared in mollusks. Furthermore, our investigations showed that there is not any single gene family that could be the parent group of interleukins. We postulate that several groups have diverged from older existing cytokines such as IL4 from TGFβ, IL10 from IFN, and IL28 from BCAM. Interleukin receptors were less divergent than interleukins. We found that IL1R, IL7R might have diverged from a common invertebrate protein that contained TIR domains, conversely, IL2R, IL4R and IL6R might have emerged from a common invertebrate ancestor that possessed a fibronectin domain. IL8R seems to be a GPCR that belongs to the rhodopsin-like family and it has diverged from the Somatostatin group. Interestingly, several interleukins that are known to perform a critical function for CD4+ T cells such as IL6, IL17, and IL1B have gained new functions and evolved under positive selection. Overall evolution of interleukin receptors was not under significant positive selection. Interestingly, eight interleukin families appeared in lampreys, however, only two of them (IL17B, IL17E) evolved under positive selection. This observation indicates that although lampreys have a unique adaptive immune system that lacks CD4+ T cells, they could be utilizing interleukins in homologous mode to that of the vertebrates' immune system. Overall our study highlights the evolutionary heterogeneity within the interleukins and their receptor superfamilies and thus does not support the theory that interleukins evolved solely in jawed vertebrates to support T cell function. Conversely, some of the members are likely to play conserved functions in the innate immune system.

Therapeutic Anti-Tumor Immunity Mediated by Transiently Engrafting Allogeneic Lymphocytes: The “Allogeneic Effect” Revisited.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5255-5255
Author(s):  
Heather J. Symons ◽  
M. Yair Levy ◽  
Jie Wang ◽  
Xiaotao Zhou ◽  
Ephraim J. Fuchs
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Host Immune System ◽  
Tumoricidal Activity ◽  
Tumor Bearing ◽  
Anti Tumor Activity ◽  
Allogeneic Lymphocytes

Abstract The “allogeneic effect” refers to the induction of host B cell antibody synthesis or host T cell cytotoxicity, including tumoricidal activity, by an infusion of allogeneic lymphocytes. We have previously shown that treatment of mice with cyclophosphamide (Cy) followed by infusion of CD8+ T cell-depleted allogeneic spleen cells (Cy + CD8− DLI) induces anti-tumor activity in a model of minimal residual leukemia, even though the donor cells are eventually rejected by the host immune system. The purpose of the current investigation was to test the activity of Cy + CD8− DLI in the treatment of well-established cancer, and to characterize the mechanisms of the anti-tumor effect. BALB/c mice were inoculated intravenously (IV) with the syngeneic A20 lymphoma/leukemia or the RENCA renal cell carcinoma on day 0 and were then treated with nothing, Cy alone on day 14, or Cy + CD8− DLI from MHC-mismatched C57BL/6 donors on day 15. In both tumor models, the combination of Cy + CD8− DLI significantly prolonged survival compared to mice treated with nothing or with Cy alone. While depletion of CD4+ T cells from the DLI significantly diminished the beneficial effect of CD8− DLI, purified CD4+ T cells alone were inactive, demonstrating that donor CD4+ T cells and another population of cells were required for optimal anti-tumor activity. Several observations pointed to an active role for the host immune system in the anti-tumor activity of Cy + CD8− DLI. First, host T cells participated in the anti-tumor effect of treatment with Cy alone, since the drug’s activity was diminished in tumor-bearing scid mice or in normal BALB/c mice depleted of T cells. Second, while Cy + CD8− DLI caused no GVHD in tumor-bearing but immunocompetent BALB/c recipients, it caused fatal acute GVHD in either tumor-bearing scid or T-cell depleted BALB/c mice. Finally, the anti-tumor effect of Cy + CD8- DLI was also significantly inhibited in BALB/c mice that were depleted of CD8+ T cells. These results demonstrate that transiently engrafting T cells administered after Cy can induce significant anti-tumor effects against both solid and liquid tumors. We propose that upon recognition of alloantigen on host antigen-presenting cells (APCs), allogeneic donor CD4+ T cells deliver activating ligands to the APCs, thereby generating effective “help” to break tolerance in tumor-specific host CD8+ T cells. This mechanism may correspond to the “allogeneic effect” in the anti-tumor response described over three decades ago.

Induction and Break of Immune Tolerance to Human FVIII in a HLA-DRB1*1501 Humanized Hemophilic Mouse Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2280-2280
Author(s):  
Katharina Nora Steinitz ◽  
Brigitte Binder ◽  
Christian Lubich ◽  
Rafi Uddin Ahmad ◽  
Markus Weiller ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Mouse Model ◽  
Mhc Class Ii ◽  
Immune Tolerance ◽  
Cd4 T Cells ◽  
Hemophilia A ◽  
Class Ii ◽  
T Cell Epitopes

Abstract Abstract 2280 Development of neutralizing antibodies against FVIII is the major complication in the treatment of patients with hemophilia A. Although several genetic and environmental risk factors have been identified, it remains unclear why some patients develop antibodies while others do not. Understanding the underlying mechanisms that drive the decision of the immune system whether or not to make antibodies against FVIII would help to design novel therapeutics. We used a new humanized hemophilic mouse model that expresses the human MHC-class II molecule HLA-DRB1*1501 on the background of a complete knock out of all murine MHC-class II genes. Initial studies had indicated that only a fraction of these mice developed antibodies when intravenously (i.v.) treated with human FVIII. These findings which resemble the situation in patients with severe hemophilia A, evoked the question if the lack of antibody development in non-responder mice reflects the induction of specific immune tolerance after i.v. application of FVIII or represent non-responsiveness for other reasons. We addressed this question by choosing another application route (subcutaneous, s.c.) and by combining i.v. application with a concomitant activation of the innate immune system applying LPS, a well characterized ligand for toll-like receptor 4, together with FVIII. Both strategies resulted in the development of antibodies in all mice included in the study what suggested that non-responsiveness against i.v. FVIII does not reflect an inability to develop antibodies against FVIII. Next, we asked if i.v. FVIII does induce immune tolerance in non-responder mice. We pretreated mice with i.v. FVIII, selected non-responder mice and challenged them with s.c. FVIII. None of the mice developed antibodies what indicated that i.v. pretreatment had induced immune tolerance in non-responder mice. Currently, we test the hypothesis that immune tolerance after i.v. application is induced and maintained by FVIII-specific regulatory T cells. The differences in responder rates after i.v. and s.c. application of FVIII raised the question if there are differences in FVIII T-cell epitopes involved in the initial activation of FVIII-specific CD4+ T cells. We obtained spleen cells from mice treated with either i.v. or s.c. FVIII and generated CD4+ T-cell hybridoma libraries that were tested for peptide specificities. For this purpose we used a FVIII peptide library containing 15 mers with an offset of 3 amino acids. Our results indicate that the pattern of FVIII-specific T-cell epitopes involved in the activation of FVIII-specific CD4+ T cells after i.v. and s.c. application of FVIII is almost identical and represents a small set of FVIII peptides distributed over the A1, A2, B, A3 and C1 domains. Based on our results we conclude that the new HLA-DRB1*1501 hemophilic mouse model represents an interesting opportunity to uncover the mechanisms that drive the decision of the immune system whether or not to develop antibodies against FVIII. Disclosures: Steinitz: Baxter BioScience: Employment. Binder:Baxter BioScience: Employment. Lubich:Baxter BioScience: Employment. Ahmad:Baxter BioScience: Employment. Weiller:Baxter BioScience: Employment. de la Rosa:Baxter BioScience: Employment. Schwarz:Baxter BioScience: Employment. Scheiflinger:Baxter BioScience: Employment. Reipert:Baxter Innovations GmbH: Employment.

Single Cell Analysis of Factor VIII-specific T Cells in Hemophilic Mice after Treatment with Human Factor VIII

2002 ◽  
Vol 87 (02) ◽  
pp. 266-272 ◽  
Author(s):  
Maria Sasgary ◽  
Rafi Ahmad ◽  
Peter Turecek ◽  
Birgit Reipert ◽  
Hans Schwarz
Keyword(s):  
T Cells ◽  
Factor Viii ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Specific Cell ◽  
Dominant Type ◽  
Intracellular Cytokines ◽  
Human Factor Viii ◽  
Ifn Γ

SummaryA multi-parameter flow-cytometry assay was established suitable for analyzing T-cell-specific cell surface markers (CD3, CD4) together with intracellular cytokines on a single cell level. This assay was used to identify the frequency and the kinetic of different populations of factor VIII (FVIII)-specific CD4+ T cells in hemophilic E-17 mice after treatment with human FVIII. A clear temporal correlation was found between the appearance of FVIII-specific CD4+ T cells in the spleen and the detection of anti-FVIII antibodies in plasma. These cells and antibodies were detectable in all experiments after two doses of FVIII and in a few even after a single dose. The IFN-γ- producing T cells were the most prominent type of FVIII-specific T cells suggesting Th1-type T cells have an important role in regulating the anti-FVIII immune response in E-17 mice. IL-10-producing T cells were the second most dominant type. They were detectable after two doses of FVIII and increased in frequency after four. Cytokine co-expression studies analyzing IL-10 and IFN-γ- in the same cell indicated that there might be at least two types of IL-10 positive T cells, those cells that produce IL-10 only and in addition cells that produce IL-10 and IFN-γ-. Furthermore, FVIII-specific T cells producing IL-2 were found in all experiments after two doses of FVIII. In a few experiments IL-4-producing T cells were seen but in most experiments they were not detectable. In contrast, IL-4 could be found in supernatants of in vitro restimulated CD8– spleen cells.

scholarly journals Imbalance of Peripheral Lymphocyte Subsets in Patients With Ankylosing Spondylitis: A Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong Liu ◽  
Budian Liu ◽  
Churong Lin ◽  
Jieruo Gu
Keyword(s):  
T Cells ◽  
Immune System ◽  
Ankylosing Spondylitis ◽  
Subgroup Analysis ◽  
Cd4 T Cells ◽  
Innate Immune System ◽  
Lymphocyte Subsets ◽  
Meta Analysis ◽  
Innate Immune ◽  
Healthy Controls

Ankylosing spondylitis is a complicated consequence of genetic predisposition and environmental factors. Enthesitis is believed to be the hallmark of ankylosing spondylitis, and the chronic inflammatory state of this disease is perpetuated by the disturbances of both the innate immune system and the acquired immune system. To clarify the alteration of immune system in patients with AS, we conducted a meta-analysis concerning the proportions of major lymphocyte subsets in the peripheral blood of AS patients. We systematically searched PubMed and China National Knowledge Infrastructure (CNKI) for articles related to this subject. A total of 95 articles involving 4,020 AS patients and 3,065 healthy controls were included in the analysis. This meta-analysis is performed on R platform using R package “meta”, and Egger’s tests were used to determine the presence of publication bias. Results showed that the percentages of T cells, NK cells and NKT cells were not significantly different between AS patients and healthy controls, but B cells were significantly increased. Among the subsets of T cells, the proportions of CD4+ T cells, Th17 cells, Tfh cells as well as Th1/Th2 ratio were significantly increased, while Tregs were significantly decreased. Subgroup analysis showed that the proportions of Th17 among both PBMCs, T cells and CD4+ T cells were significantly elevated, while Tregs were only significantly lower in PBMCs. Subgroup analysis also demonstrated that Tregs defined by “CD4+CD25+FoxP3+”, “CD4+CD25+CD127low”or “CD4+CD25+CD127-”were significantly downregulated, indicating that the selection of markers could be critical. Further study is warranted in order to elucidate the complicated interactions between different lymphocyte subsets in AS patients. This study implied that the disequilibrium between Th17 and Tregs, as well as between Th1 and Th2 could contribute to the pathogenesis of ankylosing spondylitis, further cementing the understanding that ankylosing spondylitis is a consequence of disrupted balance of innate immune system and acquired immune system.

Generation of GMP-Grade CMV pp65-Specific CD8+ and CD4+ Donor T Cell Lines for Treatment of CMV Reactivation after Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2931-2931
Author(s):  
Maarten L. Zandvliet ◽  
J.H. Frederik Falkenburg ◽  
Inge Jedema ◽  
Roelof Willemze ◽  
Henk-Jan Guchelaar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Cd4 T Cells ◽  
Target Cells ◽  
Specific Cell ◽  
Specific Response ◽  
Specific Lysis ◽  
T Cell Lines

Abstract Reactivation of CMV remains a major cause of morbidity and mortality in immunocompromised recipients of allogeneic stem cell transplantation. Antiviral pharmacotherapy may not be sufficient due to significant toxicity and moderate efficacy. It has been shown that adoptive transfer of donor-derived CMV-specific T cells may be an effective strategy to control established CMV infection. For a persistent function in vivo the presence of both virus-specific CD8+ and CD4+ T cells is essential. Therefore, we developed an optimized protocol for the generation of CMV pp65-specific CD8+ and CD4+ T cell lines which is fully compliable with Good Manufacturing Practice (GMP) conditions. Enrichment for CMV-specific T cells followed by only a short culture period is likely to retain maximal in vivo potential. PBMCs from 7 CMV seropositive donors were stimulated with recombinant pp65 protein (7–70 μg/ml) and/or HLA-A*0201/HLA-B*0702 restricted immunodominant pp65 peptides (NLV/TPR). Peptides used were clinical grade, and recombinant protein was gamma-irradiated (50 kGy, −80 C°) to eliminate possible microbiological contamination. High dose gamma-irradiation of pp65 protein resulted in partial degradation, but antigenic presentation was maintained. IFNγ producing cells were enriched using the IFNγ secretion assay (Miltenyi Biotec) at day 1 after stimulation, and cultured with autologous feeders (10x) and IL-2 (10 or 50 IU IL-2/ml) with or without CD3/28 expansion beads. Addition of high concentrations of protein during initial stimulation had a negative effect on enrichment probably due to non-specific stimulation of cells. Addition of immunodominant pp65 peptides promoted isolation efficiency and proliferation of epitope-specific CD8+ T cells in some donors. Cell lines were analyzed at different time points (day 4–15) using peptide-MHC tetramer and phenotypic markers. In addition, pp65-specificity was evaluated by intracellular IFNγ staining after restimulation with a pp65 protein-spanning pool of 15-mer peptides. CMV-specific lysis was tested in a 51-Cr release assay on pp65-transduced target cells. Enrichment of IFNγ producing cells after pp65 protein stimulation resulted in pp65-specific cell lines consisting of both CD8+ and CD4+ T cells. The T cell subset distribution directly after enrichment did not change during culture and was reproducible for each donor. Moreover, the composition of T cell lines reflected the pp65-specific response in donor PBMC starting material. The CD8+ compartment contained the known immunodominant tetramer staining cells (range 5–100%). The majority of both CD8+ and CD4+ T cells produced IFNγ upon restimulation with the pp65 peptide-pool, and showed CMV-specific lysis of target cells. The phenotype of pp65-specific T cells was predominant CD28+/CD45RO+ and CD45RA−/CCR7−/CD62L−, although CCR7 and CD62L were transiently expressed at day 4 and 7 after stimulation. Cryopreservation did not affect the composition or functionality of T cell lines. In conclusion, this procedure yields GMP-grade T cell lines comprising both CD8+ and CD4+ CMV-specific T cells. Processing and presentation of CMV protein by donor antigen-presenting cells enables selection of the full pp65-specific donor repertoire, without restrictions related to HLA or known epitopes. The choice for a moderate or more vigorous expansion after enrichment remains arbitrary and needs to be evaluated in clinical trials.

Treatment of Established B16 Murine Melanoma Tumors with Tyrp-1 Specific CD4+ Lymphocytes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3688-3688
Author(s):  
Pawel Muranski ◽  
Andrea Boni ◽  
Crystal M. Paulos ◽  
Kari R. Irvine ◽  
Paul A. Antony ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Solid Tumors ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Tumor Response ◽  
Class Ii ◽  
B16 Melanoma ◽  
Cd4 Cells

Abstract T-cell mediated response against solid tumors has been mostly associated with CD8+ cytotoxic lymphocytes, which act directly on the MHC class I expressing tumors. In the previously published model, gp-100 melanoma antigen-specific pmel-1 CD8+ T cells required co-administration of IL-2 and vaccine to induce significant regression of poorly immunogenic B16 melanoma in mice. MHC class II restricted CD4+ T-cells (T helpers) may have multiple direct and indirect effects on the immune response, but their role in adoptive cell transfer (ACT) therapy of solid tumors remains mainly undefined and based on highly manipulated models involving foreign antigens. In order to investigate the function of tumor specific CD4+ T-cells we have generated a transgenic mouse expressing a TRP-1 T cell receptor (TCR) directed against class II restricted murine melanocyte differentiation antigen tyrp-1. In vitro expanded TRP1 CD4+ cells secreted Th1-like cytokines upon antigen stimulation and caused direct cytotoxic effect against B16 melanoma. In vivo they mediated a highly effective response against large (>1cm2) B16 melanoma tumors after ACT of as few as 2.5×105 cells/mouse into C57B6 animals, which was associated with a massive tumor infiltration with CD11b+, MAC3+, GR1+ cells. TRP-1 T cells caused partial tumor rejection and prolonged survival in MHC class II−/− hosts implying the ability to directly recognize low level MHC class II on the tumor. This suboptimal effect was significantly enhanced after co-transfer of MHC class II+ APCs into MHC class II−/− hosts allowing for antigen cross- presentation. Interestingly, Rag1−/− hosts, deficient in all T and B lymphocytes, demonstrated excellent initial response to treatment, but were not cured and succumbed to late relapse of the melanoma. Long-term responses were even more impaired in Rag1−/− γc−/− hosts, while complete and durable cure was observed in TCRα−/−, CD4−/− and C57B6 mice, suggesting involvement of other arms of the adaptive immune system. Similarly, co-transfer of 0.1×106 CD4+ TRP-1 cells and 1×106 CD8+ pmel-1 cells resulted in effective tumor regression, while the same numbers of each cells transferred individually were not sufficient to initiate a rejection. Introduction of tumor-specific CD4+ cells therefore eliminates the previously sine qua non need for co-administration of vaccine and IL-2 for effective treatment with CD8+ pmel-1 cells. Overall, we show that antigen-specific CD4+ T cells are highly effective in mediating the anti-tumor response by causing both the direct anti-tumor effect and by activating innate and adaptive arms of the immune system. These findings suggest that CD4+ T helper cells may play a key role in improving efficacy of ACT immunotherapy as central activators of the anti-tumor response.

CD4+ T-Cell Functions Are Modulated by the Extracellular ATP Concentration

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2190-2190
Author(s):  
Sara Trabanelli ◽  
Darina Ocadlikova ◽  
Sara Gulinelli ◽  
Marco Idzko ◽  
Antonio Curti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Conflicts Of Interest ◽  
Extracellular Atp ◽  
Extracellular Nucleotides ◽  
Cd4 T Cell ◽  
Specific Cell ◽  
Cell Functions ◽  
Atp Concentration

Abstract Abstract 2190 Adenosine 5'-triphosphate (ATP) plays a pivotal role in several cellular processes, through specific cell membrane purinergic P2 receptors (P2Rs). During inflammation and tumor cell growth, cell necrosis causes the release of intracellular ATP into the extracellular space, thus increasing from low (1–10 nM) to high (5–10 mM) the concentration of extracellular ATP. For this reason, variations in the extracellular ATP concentration might activate/inhibit the immune system. Here we investigated the role of ATP on CD4+ T-cell functions. We first demonstrated the expression of P2Rs for extracellular nucleotides in human activated CD4+ T cells and regulatory T cells (Tregs) We then show that physiological concentrations of extracellular ATP (i.e. 1–50 nM) do not affect both activated CD4+ T cells and Tregs. Conversely, supraphysiological concentrations of ATP show a bimodal effect on activated CD4+ T cells. Whereas 250 nM of ATP stimulates proliferation, cytokine release, expression of adhesion molecules and adhesion, high ATP concentration (i.e. 1 mM) induces apoptosis and inhibits activated CD4+ T-cell functions. On the contrary, at the same high concentration, ATP enhances the proliferation, adhesion, migration and immunosuppressive ability of Tregs. Similar results are obtained when activated CD4+ T cells and Tregs are exposed to ATP released by necrotized leukemic blasts. The present results provide evidence that different concentrations of extracellular ATP modulate T cells according to their activation status. Therefore, high concentrations of ATP, compatible with fast-growing tumors or hyper-inflamed tissues, may have a key role in killing activated CD4+ T cells and in expanding Tregs. Disclosures: No relevant conflicts of interest to declare.

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