scholarly journals Deficiency of CD4 T cells Contributes to Cardiac Fibrosis and Myocardial Dysfunction in T cell Specific S1P Receptor 1 Knockout Mice

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Zhuqiu Jin ◽  
Chowdhury Abdullah
Keyword(s):  
T Cells ◽  
T Cell ◽  
Knockout Mice ◽  
Cd4 T Cells ◽  
Cardiac Fibrosis ◽  
Myocardial Dysfunction ◽  
S1p Receptor

Abstract 16615: Reconstitution of CD4 T Cells Causes Cardiac Fibrosis and Myocardial Dysfunction in T Cell Specific S1P Receptor 1 Deficient Diabetic Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Chowdhury S Abdullah ◽  
Zhu-Qiu Jin
Keyword(s):  
T Cells ◽  
Body Weight ◽  
T Cell ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Cardiac Fibrosis ◽  
Myocardial Dysfunction ◽  
Diabetic Mice ◽  
Knock Out ◽  
S1p Receptor

Involvement of T cells in fibrosis has been reported but modulation of their role in context of diabetic fibrogenesis has yet to be determined. Our previous studies indicated that T cell S1P receptor 1 (S1P1) genetic depletion ensues sustained lymphopenia in circulation and reduced fibrosis in streptozotocin-induced type 1 murine diabetic model. We hypothesized that adoptive transfer of T cells to T-cell S1P1 receptor knock-out (TS1P1KO) mice would abolish cardioprotection and antifibrotic effect as observed earlier. TS1P1KO and littermate wild-type (WT) mice were divided into vehicle and streptozotocin (STZ) (50 mg/kg body weight for five days, i.p.) groups. Naïve CD4 T cells were isolated by positive selection through MS column from CD4 magnetic microbeads-labeled WT mice splenocytes. Isolated CD4 T cells (purity >95%) were adoptively transferred (i.v.) into the mice of above groups at dose of one million cells. Body weight (g) and blood glucose level (mg/dl) were monitored. CD4 and CD8 T cells in blood were counted by flow cytometry. Heart histology was studied in H&E stained sections and pathological grading was given. Masson Trichrome stained heart sections were digitally imaged at 16x magnification and percent of fibrotic area was quantified by using NIH ImageJ. Cardiac contractility was measured in ex-vivo Langendorff’s heart perfusion system at the end of 11 weeks. TS1P1KO mice had ~90% reduced T cells (CD4 cells: 1.15±0.30% vs 25.06±0.64%, CD8 cells: 2.09±0.42% vs 14.72±0.38% in WT, **P<0.01, n=4-5) in blood. KO diabetic mice without adoptive transfer of CD4 T cells exhibited about 70% less fibrotic area (11.86±4.34% vs 46.48±8.06% in WT STZ, *P<0.05, n=7-9) and improved cardiac structure and function. Adoptively CD4 T cells recipient KO diabetic mice presented cardiac structural disorganization (histological score: 9.25±0.95 vs. 1.29±0.52 in KO STZ without transfer, *P<0.05, n=4-7) and increased myocardial fibrosis (37.11±3.22% vs. 11.86±4.34% in KO STZ without transfer, *P<0.05, n=4-7) with reduced cardiac contractile force compared with KO diabetic mice without CD4 T cells transfer. In conclusion, reconstitution of CD4 T cells increases cardiac fibrosis and attenuates cardiac function in lymphopenic T cell S1P1 knock-out diabetic mice.

Abstract 273: T cell Sphingosine 1-Phosphate Receptor 1 Signaling Possesses Intrinsic Anti-fibrotic Effects in Murine Heart

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhuqiu Jin ◽  
Chowdhury S Abdullah
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Fibrosis ◽  
Myocardial Dysfunction ◽  
Critical Role ◽  
Contractile Force ◽  
Conditional Knockout ◽  
Cell Trafficking ◽  
Tgf Beta ◽  
Cardiac Contractile

T lymphocyte infiltration into myocardium has been observed in patients with myocardial infarction and diabetic cardiomyopathy. T cell trafficking from primary lymphoid organs into blood depends on S1P receptor 1 (S1P 1 ) activation and S1P concentration gradients. However, effects of T cell S1P 1 signaling activation on cardiac fibrosis and function remain unknown. Mice with conditional knockout of T cell S1P 1 were generated by cross-bred of S1P 1 loxp-loxp mice with Lck-Cre transgenic mice. T cell S1P 1 mutant mice (TS1P 1 KO) and wildtype littermate (WT) were utilized. To explore the effect of T cell S1P 1 on cardiac fibrosis and myocardial function, additional groups with reconstitution of T cells containing S1P 1 were conducted by injection of freshly prepared T cells from WT into TS1P 1 KO. Body weight, glucose levels, and behavior change were recorded twice a week. After 11 weeks, Langendorff heart perfusion was prepared. Cardiac contractile force was recorded. Trichrome staining was used to evaluate the extent of cardiac fibrosis. CD4, CD8, and Foxp3 regulatory T cells in the blood and spleen were quantified with flow cytometry. Expression of TGF-beta and CD34 in mouse myocardium was determined by using immunohistochemistry. Comparing with WT control, TS1P 1 KO mice exerted increased cardiac fibrosis and low cardiac contractile force (P<0.05). TGF-beta expression and CD34 stained cells were significantly enhanced in TS1P 1 KO mice. Both CD4 and CD8 T cells in the blood and spleen were reduced significantly in TS1P 1 KO. Reconstitution of T cells with S1P 1 into TS1P1KO attenuated cardiac fibrosis and myocardial dysfunction. In conclusion, T cell S1P 1 signaling plays a critical role in anti-fibrosis and cardioprotection.

scholarly journals Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Stephanie M. Dillon ◽  
Tezha A. Thompson ◽  
Allison J. Christians ◽  
Martin D. McCarter ◽  
Cara C. Wilson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Older Persons ◽  
Age Groups ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Cell Immunity ◽  
Memory Cd4 T Cells

Abstract Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

scholarly journals The Impact of Exercise Serum on Selected Parameters of CD4+ T Cell Metabolism

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 119-131
Author(s):  
Jana Palmowski ◽  
Kristina Gebhardt ◽  
Thomas Reichel ◽  
Torsten Frech ◽  
Robert Ringseis ◽  
...  
Keyword(s):  
T Cells ◽  
Oxygen Consumption ◽  
T Cell ◽  
Real Time ◽  
Cd4 T Cells ◽  
Cell Metabolism ◽  
Cd4 T Cell ◽  
Autologous Serum ◽  
Cell Phenotype ◽  
The Impact

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.

scholarly journals Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rhianna Jones ◽  
Kyle Kroll ◽  
Courtney Broedlow ◽  
Luca Schifanella ◽  
Scott Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Rhesus Macaques ◽  
Oral Microbiome ◽  
Probiotic Supplementation ◽  
Siv Infection ◽  
Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

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.

scholarly journals THU0046 A PIPELINE TO STUDY ANTIGEN-SPECIFIC CD4+ T CELLS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 235.1-236
Author(s):  
R. Kumar ◽  
N. Yoosuf ◽  
C. Gerstner ◽  
S. Turcinov ◽  
K. Chemin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Tenascin C ◽  
Tetramer Staining ◽  
Tcr Repertoire ◽  
Citrullinated Antigen

Background:Autoimmunity to citrullinated autoantigens forms a critical component of disease pathogenesis in rheumatoid arthritis (RA). Presence of anti-citrullinated protein antibodies (ACPAs) in patients has high diagnostic value. Recently, several citrullinated antigen specific CD4+T cells have been described. However, detailed studies of their T-cell receptor usage and in-vivo profile suffer from the disadvantage that these cells are present at very low frequencies. In this context, we here present a pipeline for TCR repertoire analysis of antigen-specific CD4+T cells from RA patients, including both citrulline and influenza (control) specificities using in-vitro peptide challenge induced-cell expansion.Objectives:To enable studies of the T cell repertoire of citrullinated antigen-specific CD4+T cells in rheumatoid arthritisMethods:Peripheral blood mononuclear cells (PBMCs) (n=7) and synovial fluid mononuclear cells (SFMCs) (n=5) from HLA-DR*0401-postive RA patients were cultured in the presence of citrullinated Tenascin C peptide cocktails or influenza peptides (positive control). Citrulline reactive cells were further supplemented with recombinant human IL-15 and IL-7 on day 2. All cultures were replenished with fresh medium on day 6 and rIL-2 was added every 2 days from then. Assessment of proportion of peptide-HLA-tetramer positive cells was performed using flow cytometry whereby individual antigen-specific CD4+T cells were sorted into 96-well plates containing cell lysis buffer, followed by PCR-based alpha/beta TCR sequencing. TCR sequencing data was demultiplexed and aligned for TCR gene usage using MiXCR. Some tetramer positive cells were sorted into complete medium containing human IL-2 and PHA for expansion of antigen-specific cells. Cells were supplemented with irradiated allogenic PBMCs (30 times number of antigen specific cells). Clones of antigen specific CD4+T cells were further subjected to tetramer staining to confirm expansion of cells.Results:As evidenced by increase in frequency of tetramer positive CD4+T cells, in vitro peptide stimulation resulted in expansion of both influenza specific (Fig. 1a) and citrullinated antigen specific (Fig. 1b) CD4+T cells. Polyclonal in-vitro expansion of tenascin C tetramer positive sorted cells followed by tetramer staining further confirmed antigen specificity and enrichment for antigen specific CD4+T cells after polyclonal stimulation (Fig.1c). TCR repertoire analysis in PB and SF dataset from the first patient showed clonal expansion of influenza specific cells in both sites. Synovial fluid had more diversity of expanding clones as compared to paired PB, with few expanded clones being shared among SF and PB. We observed a more diverse TCR repertoire in citrulline specific CD4+T cells. We also observed sharing of TCR alpha chains among different citrulline specific CD4+T cell clones.Fig. 1In-vitroexpansion of antigen specific CD4+T cells:Conclusion:This method provides a highly suitable approach for investigating TCR specificities of antigen specific CD4+T cells under conditions of low cell yields. Building on this dataset will allow us to assess specific features of TCR usage of autoreactive T cells in RA.PBMCs were cultured in presence of (a) influenza (HA, MP54) and (b) citrullinated tenascin peptides. The proportion of antigen specific CD4+T cells was assessed using HLA-class II tetramer staining. We observed an increase in frequency of (a) Infleunza specific cells (red dots in upper left and lower right quadrants) and (b) citrullinated tenascin C specific cells (red dots in lower right quadrant), at day 13 post culture as compared to day 3. (c) Sorting of citrullinated tenascin specific CD4+T cells, followed by PHA expansion resulted in visible increase in proportion of citrullinated tenascin specific CD4+T cells.Disclosure of Interests:Ravi kumar: None declared, Niyaz Yoosuf: None declared, Christina Gerstner: None declared, Sara Turcinov: None declared, Karine Chemin: None declared, Vivianne Malmström Grant/research support from: VM has had research grants from Janssen Pharmaceutica

scholarly journals Upregulation of PD-1 expression on circulating CD8+ but not CD4+ T cells is associated with tuberculosis infection in health care workers

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Cui-lin Shi ◽  
Jian-ping Zhang ◽  
Ping Xu ◽  
Jin Li ◽  
Jie Shen ◽  
...  
Keyword(s):  
Health Care ◽  
T Cells ◽  
T Cell ◽  
Health Care Workers ◽  
Cd4 T Cells ◽  
Receptor Expression ◽  
Effector Memory ◽  
Care Workers ◽  
Latent Tb ◽  
Latent Tb Infection

Abstract Background Health care workers (HCWs) are at risk for occupationally acquired Mycobacterium tuberculosis infection and tuberculosis (TB) disease due to repeated exposure to workplace tubercle bacilli. To determine whether continual mycobacterial stimulation correlates with increased expression of inhibitory T cell receptors, here we compared PD-1 receptor expression on surfaces of circulating T cells between naïve (uninfected) HCWs and HCWs with latent TB infection (LTBI). Result Data collected from 133 medical workers who met study selection criteria were included in the final analysis. QuantiFERON-TB Gold In-​Tube (QFT-GIT) testing yielded positive results for 32 HCWs, for an overall LTBI rate of 24.1%. Multivariate analysis identified HCW length of service > 15 years as an independent risk factor for a positive QFT-GIT result. In addition, comparisons of blood T cell subgroup profiles between QFT- and QFT+ groups indicated QFT+ subjects possessed greater proportions of mature (TM), transitional memory (TTM) and effector memory (TEM) CD4+ T cell subgroups and lower proportions of naïve T cells (TN). Moreover, the QFT+ group percentage of CD8+ T cells with detectable surface PD-1 was significantly higher than the corresponding percentage for the QFT- group. Meanwhile, no statistical intergroup difference was observed in percentages of CD4+ T cells with detectible surface PD-1. Conclusions Our data demonstrated that upregulated PD-1 expression on circulating CD8+, but not CD4+ T cells, was associated with latent TB infection of HCWs. As compared to other hospitals, occupational TB infection risk in our hospital was substantially mitigated by implementation of multitiered infection control measures.

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