Kidney infiltrating NK cells and NK-like T cells in lupus nephritis – presence, localization and the effect of immunosuppressive treatment

Abstract Systemic lupus erythematosus (SLE) is a multi-organ inflammatory disease with kidney inflammation, lupus nephritis (LN), being one of the most severe manifestations. Immune complex deposits, particularly in glomeruli, and T cells, B cells, and myeloid cells, mainly with extraglomerular localization, contribute to the inflammatory process. Natural killer (NK) cells have been suggested to play a role in autoimmune diseases, but have not been investigated in detail in renal lupus before. In this exploratory study, we performed the first characterization of NK cell number and distribution in LN kidney biopsies. Twelve SLE patients were analysed in the active phase of disease and five patients following immunosuppressive therapy. CD56 + cells, corresponding to NK cells or NKlike T cells, were identified in all patients, however, with reduced numbers in four out of five patients at follow up. Furthermore, cells were present in the kidney interstitium and peri-glomerular areas, but only rarely in glomeruli. Fluorescent co-staining of CD56 or NKp46 and CD3 revealed the presence of both CD56 +/NKp46 +CD3 -NK cells and CD56 +/NKp46 +CD3 +NK-like T cells. Compared to healthy kidney sections, one out of four LN patients showed increased numbers of NK cells. A correlation between CD56 + or NK cells with clinical parameters could not be observed, perhaps due to the small patient cohort. In conclusion, we have identified NK cells and NKlike T cells in LN kidney and performed the first detailed analysis of their localization during active and inactive disease. Their role in LN pathogenesis is, however, unclear and deserves further studies.

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HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463200501800209 ◽

2005 ◽

Vol 18 (2) ◽

pp. 269-276 ◽

Cited By ~ 26

Author(s):

F. Martini ◽

C. Agrati ◽

G. D'Offizi ◽

F. Poccia

Keyword(s):

T Cells ◽

Hiv Infection ◽

Nk Cells ◽

Cd4 T Cells ◽

Nk Cell ◽

Treatment Interruption ◽

Cell Number ◽

Hiv Replication

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

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Costimulatory Molecule Profiles After Autologous Hematopoietic Cell Transplantation (HCT) in Multiple Myeloma (MM) Patients

Blood ◽

10.1182/blood.v118.21.5108.5108 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5108-5108

Author(s):

Myo Htut ◽

Ghislaine Gallez-Hawkins ◽

Joycelynne Palmer ◽

Xueli Liu ◽

R. Spielberger ◽

...

Keyword(s):

T Cells ◽

Nk Cells ◽

Nk Cell ◽

Costimulatory Molecule ◽

Disease Status ◽

Cell Number ◽

Costimulatory Molecules ◽

Disease Response ◽

Significant Difference ◽

Autologous Hct

Abstract Abstract 5108 Introduction: Co-stimulatory signal is antigen non-specific and is provided by the interaction of costimulatory molecules expressed on the membranes of antigen presenting cells (APC) and T/NK cells. It plays as a complementary second signal to interaction of MHC molecules on APC and T cell receptors on T cells (first signal). Costimulatory molecules can be either inhibitory or stimulatory and may play a role in MM cell growth. Blockade of these pathways may provide a new therapeutic avenue. Background: Prior studies have shown up-regulation of inhibitory pathways such as CTLA-4 and down regulation of activating CD28 in MM patients, compared to healthy controls but there was no comprehensive characterization of costimulatory functions in MM patients. This is a pilot study assessing NK cell reconstitution and expression of inhibitory molecules (PD-1 and CTLA-4) and stimulatory molecules (ICOS, 4-1BB, CD28 and OX40) before and after autologous transplantation in MM patients. Methods: Twelve adult patients with MM undergoing auto-transplant who are able to provide written informed consent are included in the study. Median age is 56.5 years (range 36 – 67). Peripheral blood samples were taken on 3–21 days prior to autologous HCT, 14, 30, 60, 90, 180 and 360 days after HCT. At the time of the current analysis, all patients were followed up to 90 days after autotransplant conditioned with high dose melphalan. Median length of follow up is 90 days post autologous HCT. A Flowcytometry method was developed in 2 six color panels to identify NK & T cells (using antibodies to CD3, CD56 & CD16) and subsets of NK cells expressing different costimulatory molecules using specific antibodies to CD28, CD152(CTLA-4), CD278(ICOS), CD134 (OX-40), CD137 (4-1BB) and CD279 (PD-1). Each panel contained 200 ul of whole blood treated with RBC lysing buffer before staining with antibodies. Clinical data were collected for disease status before and after HCT as well as the presence of documented infections. One way ANOVA test and Kruskal-Wallis test (non-parametric) were used to analyze the data. Disease status for MM was defined as per International myeloma working group guidelines. Results: Very Good Partial Response or better (≥ VGPR) was seen in 5 patients before HCT and 8 patients after HCT (best response was taken if there are different disease status in a given patient after HCT). Partial Response or worse (≤ PR) was seen in 7 patients before HCT and 4 patients after HCT. One patient had a progressive disease. NK cell number was highest (20% of total lymphocytes) at d14 (p =0.011) compared to pre HCT, d60 and d90 levels and back to pre HCT level at d90 (Figure 1). No statistically significant difference in individual costimulatory molecule expression was noted between pre-HCT vs. post-HCT periods. NK cell numbers were higher in patients with ≥VGPR compared to patients with ≤PR at d30 (p =0.004) and d60 (p =0.028) (Figure. 2). There was no significant difference in individual costimulatory molecule expression between ≥ VGPR vs. ≤ PR groups. Higher number of NK cells were noted in patients with infections up to d90 (p=0.0081). In contrast, no significant difference in individual costimulatory molecule expression was seen between patients with infections vs. no infections. Conclusion: At present analysis, we can determine that NK cell recovery is shorter (60–90 days) as opposed to CD 4 + T cells which have been shown to take about 12 months to recover after autologous HCT. Higher NK cell number were seen in patients with better disease response. There were no differences in costimulatory molecule profiles pre and post HCT based on early disease response. However, we plan long term follow up to see if this is a predictor of relapse. Disclosures: Off Label Use: in administration of plerixafor. Krishnan:Celgene: Speakers Bureau; Millenium: Speakers Bureau.

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NK Cell KIR Reconstitution after Allogeneic Hematopoietic Cell Transplant (HCT) Is Affected by T Cell Number and Function.

Blood ◽

10.1182/blood.v106.11.1406.1406 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1406-1406

Author(s):

Sarah Cooley ◽

Valarie McCullar ◽

Rosanna Wangen ◽

Tracy L. Bergemann ◽

John E. Wagner ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor ◽

Nk Cells ◽

Clinical Outcomes ◽

Nk Cell ◽

Cell Number ◽

Hematopoietic Cell ◽

Naive T Cells ◽

Naïve T Cells

Abstract NK cell KIR interactions are among the variables known to affect clinical outcomes including relapse, graft versus host disease (GVHD) and survival after HCT. We hypothesized that T cells in graft sources available for HCT may affect KIR recovery and the therapeutic potential of KIR alloreactivity. We studied KIR reconstitution (the percentage of KIR+ NK cells measured by flow cytometry) in blood collected from recipients at day +100 after T cell deplete (TCD-BMT) and unmanipulated (U-BMT) unrelated BM transplants. We found that KIR reconstitution was suppressed compared to the healthy donors, significantly more so after U-BMT transplants (donor: 48.42 ± 2.35% KIR+ NK cells versus recipient: 26.74 ± 1.94, n = 36; P < .001) than after TCD-BMT transplants (donor: 53.34 ± 3.25% versus recipient: 42.68 ± 3.32%, n = 38; P = .017), with P = .001 between the recipient groups. Additionally, multivariate Cox proportional hazards models showed that improved KIR recovery independently correlated with improved survival and that higher NK cell IFN-γ production independently correlated with more frequent acute GVHD in that patient cohort. These data suggested that T cell number in the graft affects KIR reconstitution and transplant outcome. We next examined other sources of hematopoietic cells in which T cell function may be suppressed either by growth factor mobilization (sibling donor unmanipulated peripheral blood: SibU-PB) or the innate naivety of the T cells (umbilical cord blood: UCB). KIR+ NK reconstitution on recovering cells at day +100 after all HCT graft types was significantly less than that on normal donor cells (normals 55.33 ± 1.73%, n = 124; all P < .0006). U-BMT recipients had significantly lower KIR+ NK recovery (27.31 ± 2.06%, n = 36 vs. SibU-PB: 37.58 ± 3.29%, n = 29; TCD-BMT: 42.68 ± 3.32%, n = 38; or UCB, 37.99 ± 2.54%, n = 49) when compared to all other transplant types. The highest absolute T cell inoculum, found in SibU-PB, showed KIR reconstitution similar to that of TCD-BMT, which had the lowest T cell content (p=0.29), perhaps due to the lower alloreactivity of the Sib grafts and to the G-CSF-priming which preferentially mobilizes T cells with a suppressive phenotype. Similarly, KIR reconstitution was better after UCB compared to U-BMT (P = .0027), possibly due to the more permissive interactions with naive T cells. These results suggest that reduced T cell number after T cell depletion, suppressed T cells found after growth factor mobilization, or naive T cells present in UCB grafts enhance in vivo KIR reconstitution after allogeneic HCT when compared to unmanipulated marrow grafts. Such enhanced KIR reconstitution may have clinical consequences. Graft T cells may directly compete for cytokines and growth factors, or may be a surrogate marker for other transplant factors such as the development of GVHD and the requirement for intensive post-transplant immunosuppression. Understanding these interactions will allow judicious selection of hematopoietic cell source to select for enhanced KIR recovery. For example, among unrelated unmanipulated donor grafts, KIR+ NK recovery was significantly better using UCB than adult donors and further investigation may show that this is advantageous to improve clinical outcomes.

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Activation of NK Cells Induces CD4 Expression and Allows HIV−1 Infection.

Blood ◽

10.1182/blood.v108.11.1253.1253 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1253-1253

Author(s):

Hideki Harada ◽

Yumi Goto ◽

Omar F. Dessouki ◽

Shinya Suzu ◽

Seiji Okada

Keyword(s):

T Cells ◽

Hiv Infection ◽

Nk Cells ◽

Nk Cell ◽

Cell Number ◽

Cell Contact ◽

Specific Marker ◽

Activation Markers ◽

Hiv 1

Abstract Natural killer (NK) cells play critical roles in immune surveillance without deliberate prior sensitization and restriction by major histocompatibility complex (MHC). Although function and cell number of NK cells are influenced in AIDS patients, direct interaction between HIV and NK cells is still controversial. Because steady-state NK cells are negative for CD4 which is a key molecule for HIV infection. In this study, we established a condition inducing CD4 expression and HIV-1 infection of NK cells in vitro. CD4 was expressed on NK cells co-cultured with HFWT cells (NK cell-selective stimulating feeder cells) and IL-2. There were no differences in expression level of NK receptors, adhesion molecules and cytotoxicity between CD4+ and CD4- NK cell subpopulations. However, expression of activation markers, CD25 and HLA-DR, and size/granularity of the CD4+ NK cells were higher than CD4- NK cells. CD4+ NK cells expressed co-receptors for HIV-1, CCR5 and CXCR4. Thus, CD4 is induced on NK cells by activation, and the CD4+ NK cells are the possible target for HIV. Next, we exposed HIV-1 clone (JR-FL) to the HFWT-activated NK cells, however, direct HIV infection to the NK cells was not observed. While, co-culture of activated NK cells with HIV infected T cells allowed HIV infection of NK cells. Because NK cell-specific marker, NKp46, was detected on p24+CD3-CD56+ cells but not on CD3+ cells, p24+CD3-CD56+ cells were certainly NK cells. These results demonstrate that NK cells are the targets of HIV. Altogether, our data suggest that CD4+ T cells transfer HIV to NK cells during this cell-to-cell contact, which cause the NK cells to be the long-living viral reservoirs or modify the function of NK cells in HIV-infected patients. Our novel co-culture system using activated NK cells and HIV-infected T cells is the powerful tool to study the function of NK cells on HIV infection.

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CD107a+ (LAMP-1) Cytotoxic CD8+ T-Cells in Lupus Nephritis Patients

Frontiers in Medicine ◽

10.3389/fmed.2021.556776 ◽

2021 ◽

Vol 8 ◽

Author(s):

Anika Wiechmann ◽

Benjamin Wilde ◽

Bartosz Tyczynski ◽

Kerstin Amann ◽

Wayel H. Abdulahad ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Nephritis ◽

Cd8 T Cells ◽

Lupus Erythematosus ◽

Inactive Disease ◽

Healthy Controls ◽

Systemic Lupus ◽

Altered Expression

Cytotoxic CD8+ T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8+ T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients (n = 31) and healthy controls (n = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8+ and C107a+ cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a+ on CD8+ T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ± 18.5% vs. 47.9 ± 15.0%, p = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a+CD8+ T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a+CD8+ T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a+ was significantly correlated with proteinuria. These results demonstrate that CD8+ T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a+CD8+ suggests a role in the pathogenesis of lupus nephritis.

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CD107a+ (LAMP-1) cytotoxic CD8+ T-cells in lupus nephritis patients

10.21203/rs.2.24347/v1 ◽

2020 ◽

Author(s):

Anika Wiechmann ◽

Benjamin Wilde ◽

Kerstin Amann ◽

Wayel H. Abdulahad ◽

Andreas Kribben ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Nephritis ◽

Cd8 T Cells ◽

Lupus Erythematosus ◽

Inactive Disease ◽

Healthy Controls ◽

Systemic Lupus ◽

Altered Expression

Abstract Background: Cytotoxic CD8 + T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8 + T-cells in SLE-patients in particular with lupus nephritis. Methods: Peripheral blood of SLE-patients (n=31) and healthy controls (n=21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8 + and C107a + cells by immunohistochemistry. Results: The percentages of CD107a + on CD8 + T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ±18.5 % vs. 47.9 ± 15.0 %, p=0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a + CD8 + T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a + CD8 + T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a + was significantly correlated with proteinuria. Conclusion: These results demonstrate that CD8 + T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a + CD8 + suggests a role in the pathogenesis of lupus nephritis.

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Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-03001-7 ◽

2021 ◽

Author(s):

Shannon L. McArdel ◽

Anne-Sophie Dugast ◽

Maegan E. Hoover ◽

Arjun Bollampalli ◽

Enping Hong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Blood Cell ◽

Nk Cells ◽

Red Blood Cell ◽

Safety Profile ◽

Nk Cell ◽

Cell Activity ◽

In Vivo Studies

AbstractRecombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

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T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽

10.1177/0961203319877242 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1468-1472 ◽

Cited By ~ 2

Author(s):

N Yoshida ◽

F He ◽

V C Kyttaris

Keyword(s):

T Cells ◽

T Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Cell Responses ◽

Cytokines And Chemokines ◽

Novel Approach ◽

Cell Tissue ◽

External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

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AsCas12a ultra nuclease facilitates the rapid generation of therapeutic cell medicines

Nature Communications ◽

10.1038/s41467-021-24017-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Liyang Zhang ◽

John A. Zuris ◽

Ramya Viswanathan ◽

Jasmine N. Edelstein ◽

Rolf Turk ◽

...

Keyword(s):

T Cells ◽

Nk Cells ◽

Genome Editing ◽

Nk Cell ◽

Basic Research ◽

Cell Recognition ◽

Site Specific ◽

Editing Efficiency ◽

Rapid Generation ◽

Therapeutic Cell

AbstractThough AsCas12a fills a crucial gap in the current genome editing toolbox, it exhibits relatively poor editing efficiency, restricting its overall utility. Here we isolate an engineered variant, “AsCas12a Ultra”, that increased editing efficiency to nearly 100% at all sites examined in HSPCs, iPSCs, T cells, and NK cells. We show that AsCas12a Ultra maintains high on-target specificity thereby mitigating the risk for off-target editing and making it ideal for complex therapeutic genome editing applications. We achieved simultaneous targeting of three clinically relevant genes in T cells at >90% efficiency and demonstrated transgene knock-in efficiencies of up to 60%. We demonstrate site-specific knock-in of a CAR in NK cells, which afforded enhanced anti-tumor NK cell recognition, potentially enabling the next generation of allogeneic cell-based therapies in oncology. AsCas12a Ultra is an advanced CRISPR nuclease with significant advantages in basic research and in the production of gene edited cell medicines.

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DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

Journal of Experimental Medicine ◽

10.1084/jem.20081752 ◽

2008 ◽

Vol 205 (13) ◽

pp. 2965-2973 ◽

Cited By ~ 195

Author(s):

Susan Gilfillan ◽

Christopher J. Chan ◽

Marina Cella ◽

Nicole M. Haynes ◽

Aaron S. Rapaport ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Adhesion Molecules ◽

Cd8 T Cells ◽

Nk Cell ◽

Cd8 T Cell ◽

Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

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