scholarly journals Twist1 in T Lymphocytes Augments Kidney Fibrosis After Ureteral Obstruction

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0007182020
Author(s):  
Jiafa Ren ◽  
Xiaohan Lu ◽  
Robert Griffiths ◽  
Jamie R. Privratsky ◽  
Steven D. Crowley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Cell Phenotype ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Helix Loop Helix

Background: Twist1 is a basic helix-loop-helix domain containing transcription factor that participates in diverse cellular functions including epithelial-mesenchymal transition and the cellular immune response. Although Twist1 plays critical roles in the initiation and progression of kidney diseases, the effects of Twist1 in the T lymphocyte on the progression of renal fibrosis require elucidation. Methods: 129/SvEv mice with a floxed allele for the gene encoding Twist1 or TNFα were bred with CD4-Cre mice to yield CD4-Cre+ Twist1flox/flox (Twist1 TKO) or CD4-Cre+ TNFflox/flox (TNF TKO) mice with robust but selective deletion of Twist1 or TNFα mRNA in T cells, respectively. Twist1 TKO, TNF TKO, and WT controls underwent UUO with assessment of kidney fibrosis and T cell phenotype at 14 days. Results: Compared with WT controls, obstructed kidneys from Twist1 TKO mice had attenuated extracellular matrix deposition. Despite this diminished fibrosis, Twist1 TKO obstructed kidneys contained more CD8+ T cells than in WTs. These intra-renal CD8+ T cells exhibited greater activation and higher levels of TNFα expression than those from WT obstructed kidneys. We found further that deletion of TNFα selectively from T cells exaggerated renal scar formation and injury after UUO, highlighting the capacity of T cell TNF to constrain fibrosis in the kidney. Conclusions: Twist1 in T cells promotes kidney fibrogenesis in part by curtailing the renal accumulation of TNF-elaborating T cells.

Separation of Gvhd from GVL Responses By Modulation of TCR Signaling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3822-3822
Author(s):  
Mobin Karimi ◽  
Martha Jordon ◽  
Taku Kambayashi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Leukemia Cells ◽  
Cell Phenotype ◽  
Tcr Signaling ◽  
Allogeneic Hsct

Abstract In allogeneic hematopoietic stem cell transplantation (HSCT), devising new strategies to separate GVHD and GVL responses is of critical importance. However, this is a difficult task, as GVHD and GVL rely on the same recognition of allogeneic MHC by donor-derived T cells. CD8+ T cells are key effector cells that mediate both GVHD and GVL. In mouse models of allogeneic HSCT, the infusion of donor-derived CD8+ T cells eliminates tumor growth but also causes severe GVHD. The activation of CD8+ T cells can be potentially manipulated by perturbing the signaling pathways downstream of the T cell receptor (TCR). TCR signaling depends on the formation of a proximal multimolecular complex, which is nucleated by adaptor proteins such as SLP-76. The phosphorylation of the Y145 residue of SLP-76 is critical for activation of the downstream enzyme PLCg1. As such, a YàF mutation at Y145 of SLP-76 (Y145F) causes decreased TCR-mediated signaling and attenuated T cell function. Here, we investigated how the SLP-76 Y145F mutation in CD8+T cells may impact GVHD and GVL responses in a mouse model of allogeneic HSCT. We employed a major MHC-mismatch mouse model of GVHD involving the transplantation of C57BL/6 (B6)-derived bone marrow (BM) into lethally irradiated Balb/c mice (B6àBalb/c). BM-transplanted mice were also injected with FACS-sorted CD8+ T cells either B6 wildtype (WT) mice or Y145F mice. Recipients of Y145F CD8+ T cells showed significantly (p<0.001) less weight loss, lower clinical score, and improved survival compared to mice injected with WT CD8+ T cells. Next, to determine whether the Y145F CD8+ T cells could mediate GVL effects, BM-transplanted Balb/c mice were additionally challenged intravenously with 1 x 105 luciferase-positive A20 leukemia cells. As expected, BM-transplanted Balb/c mice succumbed from A20 tumor growth, whereas mice injected with WT CD8+ T cells cleared the tumor but developed GVHD. Surprisingly, mice receiving Y145F CD8+ T cells eradicated the leukemic cells but did not develop GVHD. These data suggest that the Y145F mutation in CD8+T cells may be able to separate GVHD from GVL effects. In addition to defective TCR signaling observed in peripheral T cells of Y145F mice, a majority of Y145F KI CD8+ T cells adopt a memory-like CD44hi phenotype through exposure to high levels of IL-4 produced in the thymus of these mice. To test whether the CD44hi CD8+ T cell phenotype was necessary and/or sufficient for the separation of GVHD and GVL effects, BM-transplanted Balb/c mice were injected with FACS-sorted CD44hi or CD44lo CD8+ T cells from WT or Y145F KI mice and challenged with A20 leukemia cells. While BM-transplanted mice receiving CD44hi CD8+ T cells from Y145F mice displayed intact GVL responses without causing GVHD, mice injected with CD44lo CD8+ T cells from Y145F mice displayed impaired ability to clear the tumor cells. Moreover, recipients of CD44hi or CD44lo CD8+ T cells from WT mice cleared the tumor but exhibited severe GVHD. These findings were corroborated with data obtained with an inducible system, whereby CD8+ T cells are affected by the Y145F mutation only after full maturation and thus do not display a CD44hi phenotype (Y145F conditional knock-in mice). Bone marrow-transplanted recipients receiving Y145F conditional knock-in CD8+ T cells developed GVHD and exhibited an attenuated GVL response, suggesting that the Y145F mutation needed to be present during T cell development. Together, these data suggest that either the Y145F mutation or CD44hi phenotype alone in CD8+T cells is insufficient to separate GVHD from GVT. Our data demonstrate that perturbation of the TCR signaling pathway downstream of Y145 of SLP-76 in CD8+ T cells results in separation of GVHD from GVL effects. Experiments to mechanistically test how the Y145F signaling mutation synergizes with the CD44hi phenotype of CD8+ T cells to allow for the separation of the GVHD and GVL effects are currently underway. Our novel and unexpected finding could lead to a novel therapeutic strategy for treatment of acute GVHD after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

Genomic and immune landscape of metastatic melanoma (MM) treated with pembrolizumab (PEM).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 184-184
Author(s):  
Yada Kanjanapan ◽  
Scott Lien ◽  
Cindy Yang ◽  
Derek L. Clouthier ◽  
Sawako Elston ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Genomic Analysis ◽  
Predictive Biomarkers ◽  
Cell Phenotype ◽  
Blood Collection ◽  
Mutation Burden ◽  
Tumor Biopsies ◽  
Immune Profiling

184 Background: Predictive biomarkers for PEM in MM is an active area of research. Methods: INSPIRE (NCT02644369) is a biomarker-driven Princess Margaret Cancer Centre initiative to evaluate genomic and immunologic changes in tumor and blood of patient (pts) treated with PEM at 200 mg IV Q3W. Baseline (BL) and on treatment (post 2-3 doses of PEM) fresh tumor biopsies were collected for DNA/RNA sequencing, immune-profiling, and tumor PD-L1 expression by immunohistochemistry (QualTek), with longitudinal blood collection for immunophenotyping. Results: As of 9/2017, 11 MM pts (9 cutaneous, 1 choroidal, 1 mucosal) were enrolled. Median treatment duration was 6 months (0.75 – 14.25); 7 pts remain on study. 7/11 (64%) pts had partial response (PR), 3/11 (27%) progressive disease (PD) and 1 was not evaluable (NE) per RECIST 1.1. Based on data for 8 pts (6 PR, 2 PD), higher percentage (%) PD-1 (mean 70 vs 12%), TIGIT (82 vs 43%) and 4-1BB (23 vs 4%) positivity on CD8 T cells in tumor vs blood was seen (all p < 0.05). In BL blood, lower % TIGIT positive CD8 T cells was detected in pts with PR vs PD (38 vs 58%, p < 0.05). T cell profile of 4 pts with paired BL and post PEM samples is shown in Table 1. Mean tumor PD-L1 score was 24% (0 - 90%), with no correlation to PEM response. Genomic analysis on 8 pts (5 PR, 2 PD, 1 NE) found mean tumor mutation burden (TMB) of 538. B2M deletion was seen in 2/2 PD and 0/6 PR pts. Among pts with PRs, 4/6 (67%) had TAP1 and TAP2 amplification post PEM therapy. HLA-A and HLA-B amplifications were each found in 3/6 (50%) PR pts, with only 1 present at BL. TMB was not associated with response to PEM. Conclusions: In this exploratory analysis of MM pts treated with PEM, there was significantly discordant T cell phenotype in tumor vs blood at BL. Our findings suggest B2M deletion to be associated with PEM resistance. The observed development of HLA-A/B and TAP1/2 amplification in 50-67% pts with PR post PEM suggests potential predictive significance, although further validation is warranted. Clinical trial information: NCT02644369. [Table: see text]

scholarly journals Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Femke Stelma ◽  
Annikki de Niet ◽  
Marjan J. Sinnige ◽  
Karel A. van Dort ◽  
Klaas P. J. M. van Gisbergen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Phenotype ◽  
Memory T Cell

scholarly journals Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection

2021 ◽  
Vol 218 (8) ◽  
Author(s):  
J. Justin Milner ◽  
Clara Toma ◽  
Sara Quon ◽  
Kyla Omilusik ◽  
Nicole E. Scharping ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Small Molecule ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Cell Phenotype ◽  
Effector T Cell ◽  
Terminal Effector

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector–specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule–mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.

scholarly journals CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?

2021 ◽  
Vol 12 ◽  
Author(s):  
Rosanne D. Reitsema ◽  
Annemieke M. H. Boots ◽  
Kornelis S. M. van der Geest ◽  
Maria Sandovici ◽  
Peter Heeringa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Vessels ◽  
Cd8 T Cells ◽  
Current Knowledge ◽  
Adaptive Immune Response ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
Functional Features ◽  
And Function

Vasculitis refers to inflammation of blood vessels and can cause a variety of serious complications depending on which vessels are affected. Two different forms of vasculitis are Giant Cell Arteritis (GCA) and Granulomatosis with Polyangiitis (GPA). GCA is the most common form of vasculitis in adults affecting the large arteries and can lead to visual impairment and development of aneurysms. GPA affects small- and medium-sized blood vessels predominantly in the lungs and kidneys resulting in organ failure. Both diseases can potentially be fatal. Although the pathogenesis of GCA and GPA are incompletely understood, a prominent role for CD4+ T cells has been implicated in both diseases. More recently, the role of CD8+ T cells has gained renewed interest. CD8+ T cells are important players in the adaptive immune response against intracellular microorganisms. After a general introduction on the different forms of vasculitis and their association with infections and CD8+ T cells, we review the current knowledge on CD8+ T-cell involvement in the immunopathogenesis of GCA and GPA focusing on phenotypic and functional features of circulating and lesional CD8+ T cells. Furthermore, we discuss to which extent aging is associated with CD8+ T-cell phenotype and function in GCA and GPA.

Increased Expression of CD152 by Normal T Lymphocytes in Untreated Patients with B Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 963-963
Author(s):  
Marina Motta ◽  
Bobby Shelvin ◽  
Susan Lerner ◽  
Michael Keating ◽  
William G. Wierda
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Lymphocytic Leukemia ◽  
Peripheral Tolerance ◽  
Regulatory Function ◽  
Cell Phenotype ◽  
Costimulatory Receptor

Abstract Patient with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Despite reported increases in absolute T cell counts in untreated patients with CLL, abnormalities of T cell phenotype and function have been described as well as progressive hypogammaglobulinemia. Furthermore, defects are compounded by current treatments for the disease. Expansion and differentiation of normal antigen-specific T cells depends upon two signals: binding of the T cell receptor to antigen presented in the context of self MHC molecules and ligation of a costimulatory receptor. CD28 is the primary T cell surface costimulatory receptor and is constitutively expressed on almost all CD4+ and about 50% of CD8+ T cells. The ligands CD80 and CD86 bind CD28, thereby transducing the second enhancing signal for T cell proliferation and cytokine secretion. CD152 (CTLA-4) has homology to CD28 and binds to CD80 and CD86 with much higher affinity, but plays a critical role in the down regulating T cell responses and maintenance of peripheral tolerance. Surface CD152 is not normally expressed on resting T cells, but is induced upon activation. We hypothesized that in previously untreated patients with CLL, T cell anergy is the result of increased expression of CD152. Therefore, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from blood (N=40) and bone marrow (N=14) of previously untreated patients with CLL. Also, the activation status of these T cells was evaluated by evaluating IL-2 receptor subunit expression. CD4+ and CD8+ T cells from patients with CLL demonstrated significant increase in sCD152 and cCD152 compared to T cells from normal donors (Table 1). Table 1 Expression of CD152 by T Cells Mean % Positive T Cell Population Normal CLL P-value sCD152 N=13 N=40 CD4+ 0.8 5.0 <.01 CD4+/CD25+ 1.8 11.5 <.05 CD8+ 1.8 5.0 <.05 cCD152 N=13 N=19 CD4+ 6.9 40.4 <.01 CD4+/CD25+ 26.6 48.0 <.01 CD8+ 1.3 16.9 <.05 Furthermore, patients with CLL had an increased proportion of CD4+/CD25+/CD152+ cells. This subpopulation of T cells is known to have a regulatory function. T cells from patients with CLL (N=25) also showed an activated immunophenotype with significantly increased proportion of CD4+ and CD8+ T cells co-expressing the CD122/CD25 subunits of the IL-2 receptor compared to normal donors (N=10). No significant differences were seen in proportion or pattern of expression of these antigens between peripheral blood and bone marrow cells. These findings suggest that the T cells have been activated, however, may be primed for hyporesponsiveness and peripheral tolerance by expression of CD152. Correlations between CD152 expression and relevant clinical and biological variables were made in these previously untreated patients. The number of CD4+/CD152+ and CD4+/CD25+/CD152+ cells from patients with CLL inversely correlated with serum IgG and IgA levels. These findings suggest a further possible involvement of CD152 in the possible suppression of normal B cells in patients with CLL. The proportion of CD4+/CD25+/CD152+ cells also correlated with advanced Rai stage. In summary, T cells from patients with CLL are potentially primed for anergy by expression of CD152. Functional studies to investigate the role of CD152 and CD4+/CD25+/CD152+ cells in patients with CLL are ongoing, with the goal to develop immunotherapeutic strategies.

Increased Frequency of HTLV-1 Tax Specific CD8+ Regulatory T-Cells in HTLV-1 Infected Individuals.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3676-3676
Author(s):  
Yohann White ◽  
Makoto Yoshimitsu ◽  
Tomohiro Kozako ◽  
Kakushi Matsushita ◽  
Kimiharu Uozumi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Cell Phenotype ◽  
Specific Cell ◽  
Asymptomatic Carriers ◽  
Cell Groups ◽  
Surface Staining

Abstract Abstract 3676 Poster Board III-612 Regulatory T-cells (Tregs) mediate self-tolerance and moderate the immune response to various antigens. Their frequency and suppressive function are reduced in various autoimmune diseases like type 1 diabetes mellitus, systemic lupus, and rheumatoid arthritis, but may be excessive in certain malignancies. The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus with myriad clinical manifestations, most notably adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). We have previously described the decreased frequency and function of HTLV-1 specific CD8+ T-cells in ATLL patients compared to asymptomatic carriers (ACs) and healthy controls (HCs). We have also reported the relative exhaustion of HTLV-1 specific cytotoxic T-lymphocytes (CTLs) compared to cytomegalovirus (CMV)-specific CTLs in ACs, as demonstrated by upregulation of the co-inhibitory molecule, programmed death 1 (PD-1). Recent evidence supports the existence of CD8+ Tregs in humans, defined primarily by forkhead box P3 (FOXP3) transcription factor expression. Although a classic Treg phenotypic marker, FOXP3's aberrant expression makes it a less reliable marker in the setting of ATLL. Low expression or absence of interleukin 7 receptor (IL-7R) (CD127lo/-) on CD25+ T-cells has provided a useful alternative Treg phenotype, allowing preservation of cell viability for functional assays. Existing studies have focused mostly on CD4+ Tregs and a few on CD8+ Tregs in malignancy, but little is known about their involvement in the persistence of chronic viral infections like HTLV-1. In chronic HTLV-1 infection, FOXP3+CD25+ and CD127lo/-CD25+ Tregs comprise 8.3±4.6% and 8.1±4.3% of overall CD8+ T-cells, respectively (n=14). Expression of the FOXP3+CD25+ phenotype in CD8+ T-cells had a tendency towards correlation with the CD127lo/-CD25+ phenotype (r=0.561, p=0.073, n=11). Among ACs, we observed the CD127lo/-CD25+ Treg phenotype in HTLV-1 Tax-specific CD8+ T-cells (45±16.5%, n=8), which was significantly greater than CMV-specific CD8+ Tregs (25±15.8%, n=6) (p<0.05, Figure 1), as characterized by phycoerythrin-labelled HLA-A*2402 Tax301-309 or HLA-A*0201 Tax11-19 and HLA-A*24/ HLA-A*02 CMV tetramers respectively. We have demonstrated that the CD8+CD127lo/-CD25+ phenotype could be an alternative marker of CD8+ Tregs. These observations suggest that HTLV-1 specific CD8+ Tregs could be implicated in the impaired clearance of HTLV-1 infected and transformed cells. This surrogate marker may facilitate further exploration of the immunological significance of antigen specific CD8+ Tregs in chronic viral infection. Figure 1 Increased frequency of HTLV-1 tetramer-specific CD8+CD127-/loCD25+ regulatory T-cells. A) Human PBMCs were gated on lymphocytes based on forward and side light scatter, and phycoerythrin-labelled HLA-A*2402 Tax301-309 or HLA-A*0201 Tax11-19 and HLA-A*24 CMV or HLA-A*02 CMV PP65 tetramer (Medical and Biological Laboratorie, Japan) specific CD8+ T-cells analyzed for intracellular FOXP3 and/or surface staining for CD25, CD8, GITR, and CD127 or appropriate isotype controls. The above representative data is shown after subtracting immunoglobulin isotype control background. B) Proportion of cells expressing the regulatory T-cell phenotype CD127-/lo CD25+ was higher for HTLV-1 Tax-specific CD8+ T-cells compared to CMV-specific T-cells (p<0.05) among asymptomatic carriers. Horizontal black bars represent means for the respective tetramer specific cell groups. Figure 1. Increased frequency of HTLV-1 tetramer-specific CD8+CD127-/loCD25+ regulatory T-cells. A) Human PBMCs were gated on lymphocytes based on forward and side light scatter, and phycoerythrin-labelled HLA-A*2402 Tax301-309 or HLA-A*0201 Tax11-19 and HLA-A*24 CMV or HLA-A*02 CMV PP65 tetramer (Medical and Biological Laboratorie, Japan) specific CD8+ T-cells analyzed for intracellular FOXP3 and/or surface staining for CD25, CD8, GITR, and CD127 or appropriate isotype controls. The above representative data is shown after subtracting immunoglobulin isotype control background. B) Proportion of cells expressing the regulatory T-cell phenotype CD127-/lo CD25+ was higher for HTLV-1 Tax-specific CD8+ T-cells compared to CMV-specific T-cells (p<0.05) among asymptomatic carriers. Horizontal black bars represent means for the respective tetramer specific cell groups. Disclosures: No relevant conflicts of interest to declare.

Marrow-Infiltrating T Cells In Patients with Chronic Lymphocytic Leukemia Display Markers of Functional Impairment and Express PD-1

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2417-2417
Author(s):  
Ursula Hainz ◽  
Quinlan L. Sievers ◽  
Kristen Stevenson ◽  
Natalie R. Goldstein ◽  
David Dorfman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Immunohistochemical Staining ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Effector Memory ◽  
Cell Phenotype

Abstract Abstract 2417 Marrow is a major site of disease development and progression for chronic lymphocytic leukemia (CLL), as well as a priming site for antigen-specific T cells and a reservoir for memory T cells. To determine the extent to which T cells in the marrow microenvironment have an altered phenotype and function in CLL, we analyzed the immunophenotypic characteristics of marrow-infiltrating T cells of 18 CLL patients compared to 11 normal donors. Chemotherapy-naïve CLL patients (n=7) possessed comparable quantities of marrow T cells compared to normal donors (median CD8+ T cells/μl = CLL 904 vs normal 1247; median CD4+ T cells/μl = CLL 1975 vs normal 1110). However, we identified several aberrant characteristics among T cells infiltrating the marrow of CLL patients. First, the ratio of CD8+ to regulatory T cells (CD4+CD25+FOXP3+) was depressed (median ratio CLL 14 vs normal 41), indicating more regulatory T cells per effector T cells in CLL. Second, compared to normal marrow T cells, CLL marrow contained proportionally fewer functional effector CD8+ T cells (CD27+CD28+)(median normal 57%, CLL 48%) and more immunosenescent cells (CD27-CD28-)(median normal 21%, CLL 30%). Third, the T cell differentiation state of CLL CD8+ T cells was skewed to favor a phenotype of increased terminal differentiation (CD45RA+CCR7-)(median CLL 55% vs normal 40%), and decreased naïve (CD45RA+CCR7+) cells (median CLL 21% vs normal 31%) compared to normal donors. These differences were further accentuated in CLL samples collected within 4 months from treatment with conventional chemotherapy (n=11). Finally, by immunohistochemical staining of CLL marrow biopsies, we observed marrow-infiltrating lymphocytes to express PD-1 (mean of infiltrating T cells, untreated CLL 12%, treated CLL 35%, present even >6 months after therapy), a marker associated both with immuno-activation and inhibition. While the majority of PD-1+ CD8 T cells of normal donors (n=5) and treated CLL patients (n=4) were differentiated towards effector memory (CD45RA-CCR7-) cells (median normal 46% vs untreated CLL 16%, p=0.07; treated CLL 61%), the PD-1+ T cells from untreated CLL patients (n=5) were terminally differentiated (CD45RA+CCR7+)(median normal 23% vs untreated CLL 65%, p=0.04; treated CLL 24%). These results indicate an exhausted rather than an activated T cell phenotype in untreated patients. Paired immunophenotypic analysis on blood and marrow from the same individuals (n=9) demonstrated an increased percentage and intensity of PD-1 expression on T cells from marrow compared to blood (percentage CD8+ T cells BM vs blood p = 0.05). Interestingly, PD-1 was also detected on CLL cells (n=16) but not normal B cells (median normal 0%, vs CLL 17%, p = 0.004). The ligand for PD-1, PD-L1, was detected in the marrow vasculature by immunohistochemical staining of biopsies, suggesting that the marrow microenvironment plays a role in the induction of PD-1 associated immunosuppression. Ligation of blood PD-L1 on CLL-T cells led to a 2-fold decrease in activation (measured as CD69 expression) of CD3/CD28 stimulated patient T cells. In summary, we identify several phenotypic and functional alterations within marrow-infiltrating T cells of CLL patients. We speculate these together may contribute to impaired priming of host immunity against the tumor. The PD-1 pathway appears to be activated in CLL, especially in the setting of chemotherapeutic treatment. Since anti-PD1 antibodies are now clinically available, it may be possible to target this pathway to improve anti-tumor responses. Disclosures: No relevant conflicts of interest to declare.

scholarly journals MicroRNAs in Kidney Fibrosis and Diabetic Nephropathy: Roles on EMT and EndMT

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Daisuke Koya ◽  
Keizo Kanasaki
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Underlying Mechanism ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Small Noncoding Rnas ◽  
Fibrotic Process ◽  
Kidney Liver ◽  
Novel Drug

MicroRNAs (miRNAs) are a family of small, noncoding RNAs that regulate gene expression in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis. As a result, miRNAs emerged as major area of biomedical research with relevance to kidney fibrosis. Fibrosis is characterized by the excess deposition of extracellular matrix (ECM) components, which is the end result of an imbalance of metabolism of the ECM molecule. Recent evidence suggests that miRNAs participate in the fibrotic process in a number of organs including the heart, kidney, liver, and lung. Epithelial mesenchymal transition (EMT) and endothelial mesenchymal transition (EndMT) programs play vital roles in the development of fibrosis in the kidney. A growing number of the extracellular and intracellular molecules that control EMT and EndMT have been identified and could be exploited in developing therapeutics for fibrosis. This review highlights recent advances on the role of miRNAs in the kidney diseases; diabetic nephropathy especially focused on EMT and EndMT program responsible for the development of kidney fibrosis. These miRNAs can be utilized as a potential novel drug target for the studying of underlying mechanism and treatment of kidney fibrosis.

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