scholarly journals The impact of CD4+CD28null T lymphocytes on atrial fibrillation: a potential pathophysiological pathway

Author(s):  
Andreas Hammer ◽  
Alexander Niessner ◽  
Patrick Sulzgruber

Abstract Introduction Atrial fibrillation (AF) represents the most common cardiac arrhythmia in daily clinical practice and substantially impacts affected patients by elevation of both morbidity and mortality. Previous investigations proved that inflammatory processes are closely linked to this multifactorial pathogenesis—especially autoreactive CD4+CD28null T cells received in-depth attention. Purpose Consequently, a potential pathophysiological pathway of the impact of CD4+CD28null T lymphocytes on the development and progression AF can be outlined. Conclusion Considering the available data in the literature, it needs to be assumed that CD4+CD28null T lymphocytes are mainly involved in the development of AF and disease progression. Of utmost importance, it can be considered as the result of a T-cell-mediated auto-immune reaction among myocardial tissue. However, mechanisms which recruit CD4+CD28null cells in cardiac tissue remain unclear and need further investigation.

Author(s):  
Carla Cendón ◽  
Weijie Du ◽  
Pawel Durek ◽  
Tobias Alexander ◽  
Lindsay Serene ◽  
...  

AbstractWhile it is generally accepted that tissue-resident memory T lymphocytes protect host tissues from secondary immune challenges, it is unclear whether, and if so, how they contribute to systemic secondary immune responses. Here we show that in human individuals with an established immune memory to measles, mumps and rubella viruses, when challenged with the measles-mumps-rubella (MMR) vaccine again, tissue-resident memory CD4+ T cells are mobilized into the blood within 16 to 48 hours after vaccination. These cells then leave the blood again, and apparently contribute to the systemic secondary immune reaction, as is evident from the representation of mobilized T cell receptor Vβ clonotypes among newly generated circulating memory T lymphocytes, from day 7 onwards. Mobilization of the tissue-resident memory T cells is cognate, in that memory T lymphocytes recognizing other antigens, e.g. tetanus toxin, are not mobilized, unless they cross-react with the vaccine. These data originally demonstrate the essential contribution of tissue-resident memory T cells to secondary systemic immune responses, confirming that immunological memories to systemic pathogens are maintained (also) by tissue-resident memory T cells. In practical terms, the present work defines day 1 to 2 after antigenic challenge as a time window to assess the entire immunological T cell memory for a certain pathogen, including mobilized tissue-resident memory T cells, and its correlates of effectivity.Capsule summaryThe study demonstrates the rapid and cognate mobilization of tissue-resident memory CD4+ T cells into the blood upon antigenic rechallenge, and their contribution to secondary systemic immune responses.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
I.E Dumitriu ◽  
P Dimou ◽  
S Kaur ◽  
S Dinkla ◽  
J.C Kaski ◽  
...  

Abstract Background The precise role of inflammation in the development and perpetuation of atrial fibrillation (AF) is yet to be fully uncovered. T lymphocytes have pivotal roles in orchestrating inflammation. Specialised subsets of lymphocytes either promote or prevent inflammation. We are investigating a unique subset of lymphocytes, the CD4+CD28null T cells that expand in patients with chronic inflammation. These cells secrete high levels of pro-inflammatory cytokines and have cytolytic function. CD4+CD28null T cells are normally maintained under control by regulatory T cells (Treg), a specialised subset of T lymphocytes with suppressive function that maintain immune homeostasis and prevent pathogenic immune responses. The role of CD4+CD28null and Treg cells has not been investigated in AF. Purpose We hypothesised that in AF the balance between pro-inflammatory and regulatory T lymphocytes is skewed in favour of inflammatory T cells, which may sustain inflammation in AF. Methods Circulating CD4+CD28null T lymphocytes and Tregs were quantified by flow cytometry in paroxysmal and persistent AF patients and healthy controls (n=30). Inflammatory cytokines were quantified in serum and the function of T lymphocyte subsets was investigated using ex vivo functional assays. Results CD4+CD28null T lymphocytes were significantly increased in the circulation of AF patients compared to controls. Of note, a higher proportion of patients with persistent AF showed an increase in inflammatory CD4+CD28null T lymphocytes compared to patients with paroxysmal AF. A marked reduction in Treg cells was present in AF patients compared to controls. Functional assays showed that IL-7 and IL-15 cytokines were responsible for CD4+CD28null T lymphocyte expansion in AF patients. Conclusions We show that patients with AF have marked changes in T lymphocytes subsets: pro-inflammatory CD4+CD28null T cells increase significantly, whilst anti-inflammatory Tregs are significantly reduced. We show for the first time that the cytokines IL-7 and IL-15 are the main drivers of CD4+CD28null T cell expansion in AF patients. These novel findings may reveal novel therapeutic strategies (e.g. cytokine blockade) to re-establish the balance between pro- and anti-inflammatory mechanisms at work in AF to improve patient outcomes. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 208-208
Author(s):  
Juan F Vera ◽  
Lara Brenner ◽  
Ann M. Leen ◽  
Helen E. Heslop ◽  
Gianpietro Dotti ◽  
...  

Abstract Although flasks, bags, or rocking bioreactors can readily expand T lymphocytes after non-specific stimulation, the requirements for antigen-driven expansion of cytotoxic T lymphocytes (CTLs) are more rigorous. Antigen-specific T cells proliferate optimally only in the 2 mL wells of 24-well plates and cannot reproducibly be adapted to growth in flasks or bags. Hence, preparation of antigen-specific T cells for adoptive immunotherapy of malignancies is extremely time-consuming, requiring between 4wks and 3mths to produce sufficient cells for therapeutic purposes, and expensive (media + plastics + cytokines + man hours). The extensive manipulation required during the culturing process increases the risk of contamination. In combination, these problems obstruct the broader clinical application of antigen-specific T cells. Antigen-specific T cell growth is limited by gas exchange, nutrients and waste buildup. Bioreactors developed to provide these requirements tend to be complex, involving mechanical rocking or stirring and continuous perfusion, which increases the expense of the procedure and limits the number of products to the number of mechanical devices that can be housed and maintained. We have now explored the use of a new static mini Cell Bioreactor for antigen-specific T cell expansion. This device is essentially a flask with a gas permeable membrane supported by a plastic lattice as its base. The O2/CO2 exchange from the base allows large volumes of media to be added thereby reducing nutrient limitations and waste build-up, and consequently the manipulation required to sustain cell expansion. We tested two different sizes of Cell Bioreactor, 10 cm2 and 100 cm2 that hold a maximum of 40mL and 2000mL of media, respectively. We were able to generate and expand Epstein-Barr virus antigen-specific cytotoxic T lymphocytes (EBVCTLs) from normal donors by coculturing antigen presenting cells (APC) (1.4E+05 × cm2) with established EBV-CTL (4.3E+03 × cm2) at an optimized cell density and stimulator: responder ratio (32:1). These culture conditions induced accelerated CTL expansion (42.5 fold ±14.8 vs 3.4 fold ±1.2 within 7 days) without media change. Manipulation was restricted to cytokine addition every 3–4 days and to LCL stimulation on a weekly basis. A single 100cm2 bioreactor could produce up to 800E+06 antigen-specific T cells, which would have required approximately 320 wells in 24 well plates (>13 plates) under standard culture conditions. The CD4:CD8 T cell ratio and phenotype of the Cell Bioreactor-expanded CTLs was similar to those expanded using the conventional method (CD27 48% vs 52.4%, CD28 65.2% vs 62.2%, CD62L 53.15% vs 54.5%, CD45RO 58.1% vs 55.7%, and CD45RA 51.1% vs 54.9%). Antigen specificity, as evaluated by tetramer analysis and IFN-g ELIspot assay demonstrated no significant differences between CTL expanded by each process. Finally, cytolytic function was confirmed using a standard chromium release assay where both sources of CTL had high specific killing of the autologous EBV-transformed LCL targets (85%±12% vs 77%±19%) and minimal killing of allogeneic targets (22%±9% vs 15%±12). In summary, we have successfully utilized the new mini Cell Bioreactor technology to induce optimal in vitro antigen-specific T cell expansion with minimal handling. Future work will evaluate the impact of the accelerated expansion on differentiation and memory markers. This new system is suited to the clinical grade expansion of other cell types including suspension cell lines, and mitogen-activated T cells, as well as T cell blasts engrafted with chimeric antigen receptors.


2021 ◽  
Author(s):  
Carlos-Henrique D Barbosa ◽  
Ariel Gomes ◽  
Fabio B Canto ◽  
Layza M Brandao ◽  
Jessica R Lima ◽  
...  

Increasing attention has been directed to cytotoxic CD4+ T cells (CD4CTLs) in different pathologies, both in humans and mice. The impact of CD4CTLs in immunity and the mechanisms controlling their generation, however, remain poorly understood. Here, for the first time, we showed that CD4CTLs abundantly differentiate during mouse infection with an intracellular parasite. CD4CTLs appear in the spleen in parallel to Th1 cells, display pathogen-derived peptide-specific cytotoxicity against antigen-presenting cells and express immunoregulatory and/or exhaustion markers. We demonstrated that CD4CTL absolute numbers and activity are severely reduced in both Myd88-/- and Il18ra-/- mice. Of note, the infection of mixed-bone marrow chimeras revealed that WT, but not Myd88-/-, cells transcribe the CD4CTL gene signature and that Il18ra-/-CD4+ phenocopy Myd88-/-CD4+ T cells. Moreover, the adoptive transfer of WT CD4+GzB+ T cells to susceptible Il18ra-/- mice increased their survival. Importantly, cells expressing the CD4CTL phenotype predominate among CD4+ T cells infiltrating the infected cardiac tissue, are increased in the circulation of Chagas patients and their frequency correlates with severe cardiomyopathy. Our findings describe CD4CTLs as a major player in immune response to a relevant human pathogen and disclose T-cell intrinsic IL-18R/MyD88 signaling as a key pathway controlling the magnitude of the CD4CTL response.


2020 ◽  
Vol 8 (1) ◽  
pp. e931
Author(s):  
Cyril Laurent ◽  
Gabrielle Deblois ◽  
Marie-Laure Clénet ◽  
Ana Carmena Moratalla ◽  
Negar Farzam-kia ◽  
...  

ObjectiveWe posit that interleukin-15 (IL-15) is a relevant contributor to MS pathobiology as this cytokine is elevated in the CNS and periphery of patients with MS. We aim to investigate (1) the impact of IL-15 on T lymphocytes from patients with MS and (2) the in vivo role of IL-15 using the experimental autoimmune encephalomyelitis (EAE) mouse model.MethodsWe compared the impact of IL-15 on T lymphocytes obtained from untreated patients with MS (relapsing-remitting, secondary progressive, and primary progressive) to cells from age/sex-matched healthy controls (HCs) using multiparametric flow cytometry and in vitro assays. We tested the effects of peripheral IL-15 administration after EAE disease onset in C57BL/6 mice.ResultsIL-15 triggered STAT5 signaling in an elevated proportion of T cells from patients with MS compared with HCs. This cytokine also enhanced the production of key proinflammatory cytokines (interferon γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17, and tumor necrosis factor) by T cells from both MS and controls, but these effects were more robust for the production of IL-17 and GM-CSF in T-cell subsets from patients with MS. At the peak of EAE disease, the proportion of CD4+ and CD8+ T cells expressing CD122+, the key signaling IL-15 receptor chain, was enriched in the CNS compared with the spleen. Finally, peripheral administration of IL-15 into EAE mice after disease onset significantly aggravated clinical scores and increased the number of inflammatory CNS-infiltrating T cells long term after stopping IL-15 administration.ConclusionsOur results underscore that IL-15 contributes to the amplification of T-cell inflammatory properties after disease onset in both MS and EAE.


2021 ◽  
Vol 22 (5) ◽  
pp. 2476
Author(s):  
Kento Fujiwara ◽  
Masaki Kitaura ◽  
Ayaka Tsunei ◽  
Hotaka Kusabuka ◽  
Erika Ogaki ◽  
...  

T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is expected to improve the efficacy and toxicity of CAR-T cells, the relationship between CAR structure and CAR-T cell functions remains unclear. Here, we constructed second-generation CARs incorporating a signal transduction domain (STD) derived from CD3ζ and a 2nd STD derived from CD28, CD278, CD27, CD134, or CD137, and investigated the impact of the STD structure and signaling on CAR-T cell functions. Cytokine secretion of CAR-T cells was enhanced by 2nd STD signaling. T cells expressing CAR with CD278-STD or CD137-STD proliferated in an antigen-independent manner by their STD tonic signaling. CAR-T cells incorporating CD28-STD or CD278-STD between TMD and CD3ζ-STD showed higher cytotoxicity than first-generation CAR or second-generation CARs with other 2nd STDs. The potent cytotoxicity of these CAR-T cells was not affected by inhibiting the 2nd STD signals, but was eliminated by placing the STDs after the CD3ζ-STD. Our data highlighted that CAR activity was affected by STD structure as well as by 2nd STD signaling.


Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 119-131
Author(s):  
Jana Palmowski ◽  
Kristina Gebhardt ◽  
Thomas Reichel ◽  
Torsten Frech ◽  
Robert Ringseis ◽  
...  

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.


2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Pritesh Desai ◽  
Vikas Tahiliani ◽  
Georges Abboud ◽  
Jessica Stanfield ◽  
Shahram Salek-Ardakani

ABSTRACTRespiratory infection with vaccinia virus (VacV) elicits robust CD8+T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8+effector T cell responses remains poorly defined. We used Batf3−/−mice to investigate the impact of CD103+and CD8α+dendritic cell (DC) deficiency on anti-VacV CD8+T cell responses. We found that Batf3−/−mice were more susceptible to VacV infection, exhibiting profound weight loss, which correlated with impaired accumulation of gamma interferon (IFN-γ)-producing CD8+T cells in the lungs. This was largely due to defective priming since early in the response, antigen-specific CD8+T cells in the draining lymph nodes of Batf3−/−mice expressed significantly reduced levels of Ki67, CD25, and T-bet. These results underscore a specific role for Batf3-dependent DCs in regulating priming and expansion of effector CD8+T cells necessary for host resistance against acute respiratory VacV infection.IMPORTANCEDuring respiratory infection with vaccinia virus (VacV), a member ofPoxviridaefamily, CD8+T cells play important role in resolving the primary infection. Effector CD8+T cells clear the virus by accumulating in the infected lungs in large numbers and secreting molecules such as IFN-γ that kill virally infected cells. However, precise cell types that regulate the generation of effector CD8+T cells in the lungs are not well defined. Dendritic cells (DCs) are a heterogeneous population of immune cells that are recognized as key initiators and regulators of T-cell-mediated immunity. In this study, we reveal that a specific subset of DCs that are dependent on the transcription factor Batf3 for their development regulate the magnitude of CD8+T cell effector responses in the lungs, thereby providing protection during pulmonary VacV infection.


1983 ◽  
Vol 158 (2) ◽  
pp. 571-585 ◽  
Author(s):  
A Moretta ◽  
G Pantaleo ◽  
L Moretta ◽  
M C Mingari ◽  
J C Cerottini

In order to directly assess the distribution of cytolytic T lymphocytes (CTL) and their precursors (CTL-P) in the two major subsets of human T cells, we have used limiting dilution microculture systems to determine their frequencies. The two subsets were defined according to their reactivity (or lack thereof) with B9.4 monoclonal antibody (the specificity of which is similar, if not identical, to that of Leu 2b monoclonal antibody). Both B9+ and B9- cells obtained by sorting peripheral blood resting T cells using the fluorescence-activated cell sorter (FACS) were assayed for total CTL-P frequencies in a microculture system that allows clonal growth of every T cell. As assessed by a lectin-dependent assay, approximately 30% of peripheral blood T cells were CTP-P. In the B9+ subset (which represents 20-30% of all T cells), the CTL-P frequency was close to 100%, whereas the B9- subset had a 25-fold lower CTL-P frequency. It is thus evident that 90% and 10% of the total CTL-P in peripheral blood are confined to the B9+ or B9- T cell subsets, respectively. Analysis of the subset distribution of CTL-P directed against a given set of alloantigens confirmed these findings. CTL-P frequencies were also determined in B9+ and B9- subsets derived from T cells that had been activated in allogenic mixed leucocyte cultures (MLC). Approximately 10% of MLC T cells were CTL-P. This frequency was increased 3.5-fold in the B9+ subset, whereas the B9- subset contained only a small, although detectable number of CTL-P. Moreover, the great majority of the (operationally defined) CTL-P in MLC T cell population were found to be directed against the stimulating alloantigens, thus indicating a dramatic increase in specific CTL-P frequencies following in vitro stimulation in bulk cultures.


1977 ◽  
Vol 146 (1) ◽  
pp. 91-106 ◽  
Author(s):  
T Hamaoka ◽  
M Yoshizawa ◽  
H Yamamoto ◽  
M Kuroki ◽  
M Kitagawa

An experimental condition was established in vivo for selectively eliminating hapten-reactive suppressor T-cell activity generated in mice primed with a para-azobenzoate (PAB)-mouse gamma globulin (MGG)-conjugate and treated with PAB-nonimmunogenic copolymer of D-amino acids (D- glutamic acid and D-lysine; D-GL). The elimination of suppressor T-cell activity with PAB-D-GL treatment from the mixed populations of hapten- reactive suppressor and helper T cells substantially increased apparent helper T-cell activity. Moreover, the inhibition of PAB-reactive suppressor T-cell generation by the pretreatment with PAB-D-GL before the PAB-MGG-priming increased the development of PAB-reactive helper T-cell activity. The analysis of hapten-specificity of helper T cells revealed that the reactivity of helper cells developed in the absence of suppressor T cells was more specific for primed PAB-determinants and their cross-reactivities to structurally related determinants such as meta-azobenzoate (MAB) significantly decreased, as compared with the helper T-cell population developed in the presence of suppressor T lymphocytes. In addition, those helper T cells generated in the absence of suppressor T cells were highly susceptible to tolerogenesis by PAB-D- GL. Similarly, the elimination of suppressor T lymphocytes also enhanced helper T-cell activity in a polyclonal fashion in the T-T cell interactions between benzylpenicilloyl (BPO)-reactive T cells and PAB- reactive T cells after immunization of mice with BPO-MGG-PAB. Thus inhibition of BPO-reactive suppressor T-cell development by the BPO-v-GL- pretreatment resulted in augmented generation of PAB-reactive helper T cells with higher susceptibility of tolerogenesis to PAB-D-GL. Thus, these results support the notion that suppressor T cells eventually suppress helper T-cell activity and indicate that the function of suppressor T cells related to helper T-cell development is to inhibit the increase in the specificity and apparent affinity of helper T cells in the primary immune response. The hapten-reactive suppressor and helper T lymphocytes are considered as a model system of T cells that regulate the immune response, and the potential applicability of this system to manipulating various T cell-mediated immune responses is discussed in this context.


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