Abstract 184: Pressure Overload Activates Left Ventricular (LV) Intramyocardial Vascular Endothelial Cells and induces T Cell Infiltration into the LV

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Pilar Alcaide ◽  
Anna Grodecki-Pena ◽  
Andrew Knapp ◽  
Tanya Kershaw ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Vascular Endothelium ◽  
Pressure Overload ◽  
Left Ventricular ◽  
T Cell Subsets ◽  
Mrna Levels ◽  
Flow Conditions ◽  
Cell Recruitment

Left ventricular dysfunction and Heart Failure (HF) are associated with systemic inflammation with clinical data showing that HF patients have higher levels of circulating pro-inflammatory cytokines. Recruitment of circulating T cells to tissues across the vascular endothelium is a key event in the inflammatory response, but whether it plays a role in the heart in HF is unknown. We hypothesized that pressure overload induced HF activates cardiac endothelial cells resulting in T cell recruitment into the left ventricle (LV). Using transverse aortic constriction (TAC), quantitative flow cytometry, immunohistochemistry, qPCR and real time live cell videomicroscopy, we examined mRNA and protein expression levels of endothelial cell adhesion molecules and the presence of T cell infiltrates in the LV in vivo , and also studied the T cell interactions with primary mouse heart endothelial cells (MHEC) under flow conditions in vitro , comparing Sham and TAC operated mice (6-10/group) during the course of HF. 48h after TAC, in the pre-hypertrophic state, no differences were observed in the recruitment of T cells in the LV. Interestingly, two and four weeks after TAC, when mice developed LVH and LV dysfunction (Fractional Shortening 25±13%), E-Selectin, VCAM-1 and ICAM-1 mRNA levels were significantly upregulated in the LV as compared to Sham mice (2.3, 2.8 and 4 fold, respectively), with notable enhancement of endothelial ICAM-1 protein levels in the LV intramyocardial vessels, and T cells infiltrated in the LV in response to TAC (P≤0.05 TAC vs Sham). Furthermore, T cells isolated from mice 2 and 4 weeks after TAC adhered to MHEC under flow conditions in significantly higher numbers than T cells from Sham mice (P≤0.01 TAC vs Sham). Systemically, the frequency of three different T cell subsets in the peripheral lymphoid organs was increased in TAC vs Sham mice, indicating activation of the adaptive immune response to pressure overload. Taken together, our studies indicate that activation of the heart vascular endothelium occurs in response to pressure overload resulting in T cell recruitment into the LV. Further studies will be needed to determine in the extent to which T cell recruitment into the heart contributes to the pathogenesis of HF.

Abstract 408: The Role of the Chemokine Receptor CXCR3 - Integrin Lymphocyte Function Associated Antigen 1 (LFA1) - Intercellular Adhesion Molecule 1 (ICAM1) Axis in T Lymphocyte Mediated Cardiac Inflammation in Pressure Overload Induced Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Ane Miren Salvador ◽  
Tania Nevers ◽  
Francisco Velazquez ◽  
Mark Aronovitz ◽  
Pilar Alcaide
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Lymphocyte Function ◽  
Cell Recruitment ◽  
Mouse Tissues

Background: Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans and mice with increased circulating chemokines CXCL9, CXCL10 and CXCL11. Expression of their receptor, CXCR3, in circulating T cells is associated with disease progression in HF patients. We recently published that ICAM1 is significantly upregulated in the LV endothelium and contributes to the progression of HF by regulating T cell recruitment to the LV in a mouse model of pressure overload (PO) induced HF. As CXCR3 can signal to integrins upon chemokine recognition and induce T cell adhesion to endothelial cells under flow conditions in vitro , we hypothesize that chemokine signaling through CXCR3 contributes to LV T cell recruitment and regulates integrin dependent adhesion to ICAM1 in PO induced HF. Methods and results: We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM1 -/- mice, cardiac fibroblasts (CFB) isolated from adult C57/BL6 mice, flow cytometry and qPCR in mouse tissues and in cells cultured in vitro . The LV expression of CXCL9, 10 and 11 was upregulated in WT mice in response to 2 and 4 weeks TAC as compared to Sham, correlating with ICAM1, IL-6 and IL-1β upregulation and increased CXCR3+ T cell LV infiltration. In vitro , CFB cultured with CXCR3+ T cells or with their culture supernatants, induced CXCL9, 10 and 11, as compared to control media cultured CFB, suggesting CFB are a source of these chemokines under stress. 4 weeks post TAC in WT mice, LV recruited CXCR3+ T cells, as well as mediastinal lymph node and circulating CXCR3+ lymphocytes expressed higher levels of the integrin LFA1, the main ligand of ICAM1, than CXCR3- T cells. The same pattern was observed in systemic CXCR3+ T cells in ICAM1 -/- mice, which, in contrast to WT mice, had reduced LV infiltrated T cells. Conclusion: Our data supports a CXCR3-LFA1-ICAM1 axis being involved in non- ischemic HF. Further studies will determine the CXCR3 ligands triggering T cell LFA1 activation through CXCR3 and whether this mechanism regulates the pathology of non- ischemic HF via ICAM-1 mediated adhesion.

Abstract 406: Interaction of T Cells From Non-ischemic Heart Failure Patients With the Activated Vascular Endothelium is Dependent on Intercellular Adhesion Molecule-1

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Tania A Nevers ◽  
Francisco Velazquez ◽  
Ane Salvador ◽  
Navin Kapur ◽  
Pilar Alcaide
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
T Cell ◽  
Vascular Endothelium ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
High Affinity

Background: Increasing evidence supports a role for inflammation in the pathogenesis of chronic heart failure (HF). Our previous studies demonstrate that T cell recruitment to the heart contributes to the progression of non-ischemic pressure overload induced HF. However, clinical data describing T cell dependent mechanisms contributing to the etiology of this disorder remains unknown. We hypothesized that non-ischemic HF activates human T cells resulting in increased adhesion to the vascular endothelium and recruitment to the heart through mechanisms involving specific endothelial adhesion molecules. Methods and Results: We used T cells from non-ischemic HF patients and non-HF controls as well as left ventricular (LV) tissue from end stage HF after LV assisted device (LVAD) support. Using FACS analysis we found that systemic T cells are significantly elevated in HF patients compared to controls (p<0.05), including Th1, Th17, and Treg cells. Immunohistochemistry analysis revealed that CD3+ and CD4+ T cells infiltrate the LV of HF subjects which were not observed in control. To evaluate the mechanisms through which T cells interact with the vasculature and potentially infiltrate the heart, we used in vitro real time video microscopy under shear flow conditions and found that T cells from HF patients firmly adhered to TNF[[Unsupported Character - Symbol Font &#61537;]] activated HUVECS. Further analysis indicated that HF T cells adhered to ICAM-1, but not to VCAM-1 in higher numbers than control T cells. The surface expression levels of the integrin ligands for VCAM-1 and ICAM-1 (VLA-4 and LFA-1 respectively) were similar between both groups, however, HF T cells exhibited a highly polarized phenotype on ICAM-1 (p<0.005 vs control), suggesting LFA-1 is in its high affinity conformation in HF T cells. Conclusions: Our findings suggest that T cells are activated in non-ischemic HF and have high affinity for the activated endothelium through mechanisms involving ICAM-1- LFA-1 adhesion. Future studies will evaluate the mechanisms regulating LFA-1 activation in HF T cells and their contribution to cardiac remodeling.

scholarly journals Effects of Vitamin D Supplementation on CD4+ T Cell Subsets and mTOR Signaling Pathway in High-Fat-Diet-Induced Obese Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 796
Author(s):  
Jeong Hee An ◽  
Da Hye Cho ◽  
Ga Young Lee ◽  
Min Su Kang ◽  
So Jeong Kim ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Vitamin D Supplementation ◽  
Mtor Pathway ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Dietary Vitamin ◽  
Mrna Levels ◽  
High Fat

Obesity is associated with an impaired balance of CD4+ T cell subsets. Both vitamin D and obesity have been reported to affect the mTOR pathway. In this study, we investigated the effects of vitamin D on CD4+ T cell subsets and the mTOR pathway. Ten-week-old male C57BL/6 mice were divided into four groups and fed diets with different fat (control or high-fat diets: CON or HFD) and vitamin D contents (vitamin D control or supplemented diets: vDC or vDS) for 12 weeks. T cells purified by negative selection were stimulated with anti-CD3/anti-CD28 mAbs and cultured for 48 h. The percentage of CD4+IL-17+ T cells was higher in the vDS than vDC groups. The CD4+CD25+Foxp3+ T cells percentage was higher in HFD than CON groups. The phospho-p70S6K/total-p70S6K ratio was lower in vDS than vDC, but the phospho-AKT/total-AKT ratio was higher in vDS than vDC groups. Hif1α mRNA levels were lower in vDS than vDC groups. These findings suggest HIF1α plays an important role in vitamin-D-mediated regulation of glucose metabolism in T cells, and dietary vitamin D supplementation may contribute to the maintenance of immune homeostasis by regulating the mTOR pathway in T cells.

Abstract 424: Effector T Cells Induce Cardiac Fibroblasts Transition to Myofibroblasts & Contribute to Pressure Overload Induced Cardiac Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tania A Nevers ◽  
Ane Salvador ◽  
Francisco Velazquez ◽  
Mark Aronovitz ◽  
Robert Blanton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Effector T Cell ◽  
Naïve T Cells

Background: Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. Recently, we showed that T cell deficient mice (TCRα -/- ) do not develop cardiac fibrosis (CF) and have preserved cardiac function in the thoracic aortic constriction (TAC) mouse model of pressure overload (PO). Specifically, CD4 + T cells are activated in the cardiac draining lymph nodes and infiltrate the LV, where the Th1 and Th17 effector T cell signature transcription factors are significantly upregulated as compared with control mice. However, the T cell subsets involved and the mechanisms by which they contribute to CF and pathogenesis of non-ischemic HF remains to be determined. Thus, we hypothesize that heart infiltrated effector T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix-producing cardiac myofibroblasts. Methods and Results: Naïve or effector T cells differentiated in vitro or isolated from mice undergoing TAC or Sham surgery were co-cultured with adult C57BL/6 cardiac fibroblasts (CFB). In contrast with naïve T cells, effector T cells and PO activated T cells strongly adhered to CFB and mediated fibroblast to myofibroblasts transition as depicted by immunofluorescence expression of SMAα. Effector T cell supernatants only slightly mediated this transition, indicating that effector T cells direct contact with CFB, rather than cytokine release is required to mediate CFB transformation. Adoptive transfer of effector, but not naïve T cells, into TCRα -/- recipient mice in the onset of TAC resulted in T cells infiltration into the left ventricle and increased CF. Conclusions: Our data indicate that CD4+ effector T cells directly interact with CFB to induce CF in response to PO induced CF. Future studies will determine the adhesion mechanisms regulating this crosstalk and evaluate the pro-fibrotic mechanisms induced and whether this is a T effector cell specific subset. These results will provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of CF in non- ischemic HF.

scholarly journals Interleukin 15 Induces Endothelial Hyaluronan Expression in Vitro and Promotes Activated T Cell Extravasation through a Cd44-Dependent Pathway in Vivo

1999 ◽  
Vol 190 (1) ◽  
pp. 9-20 ◽  
Author(s):  
Pila Estess ◽  
Animesh Nandi ◽  
Mansour Mohamadzadeh ◽  
Mark H. Siegelman
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
T Cell ◽  
Microvascular Endothelial Cell ◽  
Dependent Manner ◽  
Cell Recruitment ◽  
Microvascular Endothelial ◽  
Dependent Pathway

T cell recruitment to extralymphoid tissues is fundamental to the initiation and perpetuation of the inflammatory state during immune and autoimmune responses. Interleukin (IL)-15 is a proinflammatory cytokine whose described functions largely overlap with those of IL-2. The latter is attributable in large part to its binding of the heterotrimeric receptor that contains the β and γ chains of the IL-2R in combination with an unique IL-15Rα chain. However, unlike IL-2, IL-15 and its receptor have a wide tissue and cell type distribution, including endothelial cells. Here, we examine the effect of IL-15 on hyaluronan expression by endothelial cells, and investigate its role in vivo in promoting the extravasation of antigen-activated T cells through a CD44-dependent pathway. The expression of hyaluronan on primary endothelial cells and microvascular endothelial cell lines is induced by IL-15, whereas IL-2 has no such activity. Moreover, intraperitoneal administration of IL-15 or TNF-α in the absence of other exogenous proinflammatory stimuli allows the extravasation of superantigen-stimulated T cells into this site in vivo in a CD44-dependent manner. T cell recruitment induced by IL-15 requires expression of an intact IL-2Rβ chain, indicating that IL-15 operates in this context through the traditional IL-15R. The results suggest that IL-15 can regulate endothelial cell function and thereby enables a CD44-initiated adhesion pathway that facilitates entry of activated T lymphocytes into inflammatory sites. They further demonstrate a novel role for IL-15 (distinct from any of IL-2) in regulating microvascular endothelial cell adhesive function, help to understand the role of IL-15R expression on endothelium, and further support a central position for this cytokine in orchestrating multiple sequential aspects of T cell effector function and therefore chronic inflammatory processes.

scholarly journals Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions.

1991 ◽  
Vol 113 (5) ◽  
pp. 1203-1212 ◽  
Author(s):  
Y Shimizu ◽  
W Newman ◽  
T V Gopal ◽  
K J Horgan ◽  
N Graber ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Subsets ◽  
Molecular Pathways ◽  
T Cell Adhesion

T cell adhesion to endothelium is critical to lymphocyte recirculation and influx into sites of inflammation. We have systematically analyzed the role of four receptor/ligand interactions that mediate adhesion of peripheral human CD4+ T cells to cultured human umbilical vein endothelial cells (HUVEC): T cell LFA-1 binding to ICAM-1 and an alternative ligand ("ICAM-X"), T cell VLA-4 binding to VCAM-1, and T cell binding to ELAM-1. Contributions of these four pathways depend on the activation state of both the T cell and HUVEC, and the differentiation state of the T cell. ELAM-1 plays a significant role in mediating adhesion of resting CD4+ T cells to activated HUVEC. LFA-1 adhesion dominates with PMA-activated T cells but the strength and predominant LFA-1 ligand is determined by the activation state of the HUVEC; while ICAM-1 is the dominant ligand on IL-1-induced HUVEC, "ICAM-X" dominates binding to uninduced HUVEC. Adhesion via VLA-4 depends on induction of its ligand VCAM-1 on activated HUVEC; PMA activation of T cells augments VLA-4-mediated adhesion, both in the model of T/HUVEC binding and in a simplified model of T cell adhesion to VCAM-1-transfected L cells. Unlike LFA-1 and VLA-4, ELAM-1-mediated adhesion is not increased by T cell activation. Differential expression of adhesion molecules on CD4+ T cell subsets understood to be naive and memory cells also regulates T/HUVEC adhesion. Naive T cell adhesion to HUVEC is mediated predominantly by LFA-1 with little or no involvement of the VLA-4 and ELAM-1 pathways. In contrast, memory T cells bind better to HUVEC and utilize all four pathways. These studies demonstrate that there are at least four molecular pathways mediating T/HUVEC adhesion and that the dominance/hierarchy of these pathways varies dramatically with the activation state of the interacting cells and the differentiation state of the T cell.

scholarly journals Endothelial Cell Dysfunction Is Involved in the Progression of Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3668-3668
Author(s):  
Tong Xing ◽  
Zhong-Shi Lyu ◽  
Cai-Wen Duan ◽  
Qi Wen ◽  
Hong-Yan Zhao ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Myelodysplastic Syndromes ◽  
T Cell Subsets ◽  
Leukemia Cells ◽  
Rna Seq

Abstract Background: Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis, refractory anemia, and a tendency to transform to acute myeloid leukemia (AML). Ineffective hematopoiesis progression and immune deregulation are dominating pathophysiological process of MDS. Emerging evidences showed the role of bone marrow (BM) microenvironment in MDS. In MDS murine model, integral BM microenvironment contributes to inferior hematopoietic function and disease progression. As an important component of BM microenvironment, the relationship between endothelial cells (ECs) and MDS progression remains largely unknown. Although ECs from MDS patients have been identified to have decreased supporting ability to normal hematopoietic stem cells (HSCs), the supporting ability of ECs in different clinical stages of MDS remains to be elucidated. In addition, the role of BM ECs from MDS patients in supporting leukemia cells and their immunomodulatory ability remains unclear. Aims: To determine the number and functions of BM ECs in different subtypes of MDS patients. Moreover, to explore the correlation between BM ECs and MDS progression, which may represent a potential therapeutic target for MDS patients. Methods: In the prospective cohort study, patients with multilineage dysplasia (MDS-MLD, N=15), MDS with excess blasts (MDS-EB, N=15), or AML(N=15) and healthy donors (HD, N=15) were enrolled. BM ECs were analyzed in HD and patients by flow cytometry and in situ histological analyses. The functions of BM ECs were analyzed by migration, angiogenesis capacities, levels of apoptosis and reactive oxygen species (ROS). To evaluate the supporting abilities of BM ECs on HSCs, leukemia cells and T cells, in vitro co-culture strategies were used. The levels of apoptosis, ROS and colony-forming unit-plating (CFU) efficiency of CD34+ and HL-60 cells were investigated. T cell subsets were analyzed by flow cytometry as previously reported. To further investigate the underlying mechanism of dysfunctional ECs, RNA sequencing (RNA-Seq) analyses and real time-PCR (qRT-PCR) were performed in BM ECs from HD and MDS patients with different subtypes. Results: In the current study, gradually increased BM ECs were observed from MDS-MLD, MDS-EB to AML patients. Furthermore, dysfunctional BM ECs were found with MDS progression, characterized by increased levels of migration, angiogenesis capacities, apoptosis and ROS. More importantly, BM ECs from MDS patients exhibited decreased supporting ability of HSCs whereas increased supporting ability of leukemia cells in vitro with MDS progression. After coculture with ECs, levels of apoptosis and ROS in CD34+ cells were increased whereas their CFU efficiency reduced. On the other hand, levels of apoptosis and ROS of HL-60 cells were decreased. The proliferation capacity and leukemia CFU efficiency of HL-60 cells after co-cultured with ECs were enhanced with MDS progression. Furthermore, following coculture with BM ECs, deregulated differentiation was demonstrated in T cell subsets, characterized by elevating proportion of Th2 and Treg and decreasing proportion of Th1 and Th17 with MDS progression. RNA-Seq showed that the expression profile of BM ECs from MDS-EB was closer to MDS-MLD, whereas that of MDS-EB was closer to AML. Different gene expression profiles indicated the expression of hematopoiesis and immune related genes increased in BM ECs with MDS progression. Mechanistically, the mRNA levels of CX CL12, SCF and NFKB of ECs were increased with MDS progression. Summary/Conclusion: In summary, the number of BM ECs gradually increased, BM EC dysfunction more and more severe, and the supporting abilities of BM ECs on HSCs decreased, whereas on leukemia cells increased with MDS progression. Moreover, ECs regulated the differentiation of T cells into immune tolerant cells with MDS progression. Although further validation is required, these findings indicated that the improvement of BM ECs may represent a potential therapeutic approach for MDS patients. Keywords: Myelodysplastic syndromes, endothelial cells, disease progression, ineffective hematopoiesis, immune deregulation Disclosures No relevant conflicts of interest to declare.

CD4+CD26 - T Cell Population in Classical Hodgkin Lymphoma Displays a Distinctive Regulatory T Cell Population.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 384-384
Author(s):  
Yue Ma ◽  
Lydia Visser ◽  
Tjasso Blokzijl ◽  
Geert Harms ◽  
Cigdem Atayar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Hodgkin Lymphoma ◽  
Regulatory T Cell ◽  
T Cell Subsets ◽  
Mrna Levels ◽  
Classical Hodgkin Lymphoma ◽  
Cell Type ◽  
Activated T Cell

Abstract Introduction: Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) are surrounded by a majority of infiltrating reactive cells, which mainly consists of CD4+ T cells. These T cells express several activation associated surface markers but lack expression of the T cell co-stimulatory molecule CD26. Little is known about the significance of these rosetting CD4+CD26- T cells. Methods: To characterize these T cells, CD4+CD26- and CD4+CD26+ T cells were sorted from lymph node cell suspensions from 7 cHL and 5 reactive lymph nodes (LN). Of 5 HL cases and 3 lymph nodes, parts of the cells were stimulated with PMA/ionomycin to get activated T cell subsets. mRNA profiles of activated and non-activated T cell populations were evaluated with quantitative RT-PCR for 46 selected genes. Results: We observed a higher percentage of CD4+CD26- T cells in cHL compared to reactive LN. For the non-activated T cell subsets, CD4+CD26- T cells in cHL showed higher mRNA levels of IL2RA, CTLA4, TNFRSF4 and CCR4 compared to LN. Moreover, these cells displayed low or no expression of the Th1 or Th2 related cytokines IL2, IFNγ, IL13, IL12B, IL4, IL5 and the chemoattractant receptor GPR44. Overall, the profiling results support a regulatory T (Treg) cell type for the CD4+CD26- T cells in cHL. Besides Tregs, Th17 cells may exist in cHL based on the significantly higher IL17 mRNA level for both the CD26- and CD26+ T cells in cHL than in LN. Upon activation, the lack of up-regulation of mRNA levels of most cytokine genes (IFNγ, IL2, IL8, IL21, IL17, IL13, IL12A and IL4) indicated an anergic character for the CD4+CD26− subset in cHL. Conclusion: A high proportion of CD4+CD26− T cells is characteristic for cHL. No evidence for a Th1 or Th2 cell type is found for these cells but they display a regulatory T cell phenotype. Anergy fits with the regulatory T cell profile of these cells, probably explaining the immunosuppressive mechanism involved in cHL.

Abstract 171: T Cell Mediated Immune Responses Regulate Cardiac Remodeling and Survival in Pressure Overload Induced Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Pilar Alcaide ◽  
Tania Nevers ◽  
Ane Salvador ◽  
Anna Grodecki-Pena ◽  
Andrew Knapp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Immune Response ◽  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
T Cell Response

Background: Clinical data support that inflammation and the improper regulation of the immune response are intimately associated with Heart Failure (HF), however, the type of immune response involved and whether it regulates cardiac remodeling remains largely unexplored. We hypothesize that T cell mediated immune responses and their recruitment into the heart influence cardiac remodeling and contribute to the pathogenesis of pressure overload induced HF. Methods and Results: Using quantitative flow cytometry we found that T cells infiltrated the heart as Wild-type mice (WT) developed systolic dysfunction and LV hypertrophy in response to transverse aortic constriction (TAC) (p<0.01 TAC vs Sham). Real time imaging demonstrated that T cells from TAC mice adhered to activated heart endothelial cells in higher numbers than T cells from Sham mice under physiological flow conditions in vitro (P<0.05) indicating a systemic T cell activation to pressure overload induced by TAC. Similarly, circulating T cells from patients with HF adhered more to activated human umbilical vein endothelial cells (HUVEC) than T cells from healthy volunteers. Based on these findings, we performed similar TAC studies in T cell deficient mice (TCRα -/- ). In contrast with WT TAC mice, TCRα -/- had preserved LV systolic and diastolic function (p<0.01) determined by echocardiography and hemodynamic studies, reduced LV fibrosis (p<0.001) and TGFβ1, collagen Iα and αSMA gene expression (p<0.05), and reduced LV hypertrophy and gene expression of ANP and BNP (p<0.05), but unaltered expression of SerCA. Remarkably, TCRα -/- had improved survival after 4 weeks of TAC [100%(16/16) TCRα -/- vs 73.7%(14/19) WT, p=0.023]. Ongoing studies will determine the mechanisms regulating T cell recruitment into the heart, the type of T cell response involved and its contribution to pathological remodeling of the heart. Conclusion: Our studies demonstrate that T cell immune responses and their recruitment into the LV contribute to the pathogenesis of pressure overload induced HF by mechanisms involving T cell regulation of cardiac hypertrophy and fibrosis, and open a window to develop novel therapeutic strategies to improve the structural, functional and molecular deficits of the failing heart.

scholarly journals P-Selectin and P-Selectin Glycoprotein Ligand 1 Are Major Determinants for Th1 Cell Recruitment to Nonlymphoid Effector Sites in the Intestinal Lamina Propria

2003 ◽  
Vol 198 (3) ◽  
pp. 369-377 ◽  
Author(s):  
Wael Haddad ◽  
Cristine J. Cooper ◽  
Zheng Zhang ◽  
Jeffrey B. Brown ◽  
Yuechun Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lamina Propria ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Transfer Model ◽  
Th1 Cell ◽  
Cell Recruitment

The recruitment of activated T cell subsets to sites of effector immune responses is mediated by homing receptors induced upon activation in secondary lymphoid tissue. Using an adoptive transfer model, the intestinal recruitment of CD4+ T cells activated with intraperitoneal antigen in complete Freund's adjuvant was examined. The data demonstrate that activated CD4+ T cells recruited to intestinal Peyer's patches (PP) and lamina propria (LP) up-regulate functional P-selectin glycoprotein ligand 1 (PSGL-1). Blockade of IL-12 inhibited functional PSGL-1 expression and reduced PP and LP CD4+ T cell recruitment by &gt;40%. P-Selectin blockade reduced LP recruitment of activated cells by 56% without affecting PP recruitment. Studies of mice examined 3 d after adoptive transfer of differentiated T cell subsets revealed that Th1 but not Th2 cells were recruited to small intestine PP and LP. Mucosal addressin cell adhesion molecule blockade reduced Th1 recruitment to PP by 90% and to LP by &gt;72%, whereas P-selectin blockade reduced Th1 recruitment to PP by 18% and Th1 recruitment to LP by 84%. These data suggest that IL-12–induced functional PSGL-1 expression is a major determinant for the recruitment of Th1 effector cells to noninflamed as well as inflamed intestine.

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