scholarly journals Analysis of the Long-Term Impact on Cellular Immunity in COVID-19-Recovered Individuals Reveals a Profound NKT Cell Impairment

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Jia Liu ◽  
Xuecheng Yang ◽  
Hua Wang ◽  
Ziwei Li ◽  
Hui Deng ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cellular Immunity ◽  
Cd8 T Cells ◽  
Nkt Cell ◽  
Cellular Immune System ◽  
Long Term Impact ◽  
Cellular Immune

ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affected over 120 million people and killed over 2.7 million individuals by March 2021. While acute and intermediate interactions between SARS-CoV-2 and the immune system have been studied extensively, long-term impacts on the cellular immune system remain to be analyzed. Here, we comprehensively characterized immunological changes in peripheral blood mononuclear cells in 49 COVID-19-convalescent individuals (CI) in comparison to 27 matched SARS-CoV-2-unexposed individuals (UI). Despite recovery from the disease for more than 2 months, CI showed significant decreases in frequencies of invariant NKT and NKT-like cells compared to UI. Concomitant with the decrease in NKT-like cells, an increase in the percentage of annexin V and 7-aminoactinomycin D (7-AAD) double-positive NKT-like cells was detected, suggesting that the reduction in NKT-like cells results from cell death months after recovery. Significant increases in regulatory T cell frequencies and TIM-3 expression on CD4 and CD8 T cells were also observed in CI, while the cytotoxic potential of T cells and NKT-like cells, defined by granzyme B (GzmB) expression, was significantly diminished. However, both CD4 and CD8 T cells of CI showed increased Ki67 expression and were fully able to proliferate and produce effector cytokines upon T cell receptor (TCR) stimulation. Collectively, we provide a comprehensive characterization of immune signatures in patients recovering from SARS-CoV-2 infection, suggesting that the cellular immune system of COVID-19 patients is still under a sustained influence even months after the recovery from disease. IMPORTANCE Wuhan was the very first city hit by SARS-CoV-2. Accordingly, the patients who experienced the longest phase of convalescence following COVID-19 reside here. This enabled us to investigate the “immunological scar” left by SARS-CoV-2 on cellular immunity after recovery from the disease. In this study, we characterized the long-term impact of SARS-CoV-2 infection on the immune system and provide a comprehensive picture of cellular immunity of a convalescent COVID-19 patient cohort with the longest recovery time. We revealed that the cellular immune system of COVID-19 patients is still under a sustained influence even months after the recovery from disease; in particular, a profound NKT cell impairment was found in the convalescent phase of COVID-19.

scholarly journals The analysis of the long-term impact of SARS-CoV-2 on the cellular immune system in individuals recovering from COVID-19 reveals a profound NKT cell impairment

2020 ◽  
Author(s):  
jia liu ◽  
Xuecheng Yang ◽  
Hua Wang ◽  
Ziwei Li ◽  
Hui Deng ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Annexin V ◽  
Double Positive ◽  
Peripheral Blood Mononuclear ◽  
Cellular Immune System ◽  
Cellular Immune

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects millions of people and killed hundred-thousands of individuals. While acute and intermediate interactions between SARS-CoV-2 and the immune system have been studied extensively, long-term impacts on the cellular immune system remained to be analyzed. Here, we comprehensively characterized immunological changes in peripheral blood mononuclear cells in 49 COVID-19 convalescent individuals (CI) in comparison to 27 matched SARS-CoV-2 unexposed individuals (UI). Despite recovery from the disease for more than 2 months, CI showed significant decreases in frequencies of invariant NKT and NKT-like cells compared to UI. Concomitant with the decrease in NKT-like cells, an increase in the percentage of Annexin V and 7-AAD double positive NKT-like cells was detected, suggesting that the reduction in NKT-like cells results from cell death months after recovery. Significant increases in regulatory T cell frequencies, TIM-3 expression on CD4 and CD8 T cells, as well as PD-L1 expression on B cells were also observed in CI, while the cytotoxic potential of T cells and NKT-like cells, defined by GzmB expression, was significantly diminished. However, both CD4 and CD8 T cells of CI showed increased Ki67 expression and were fully capable to proliferate and produce effector cytokines upon TCR stimulation. Collectively, we provide the first comprehensive characterization of immune signatures in patients recovering from SARS-CoV-2 infection, suggesting that the cellular immune system of COVID-19 patients is still under a sustained influence even months after the recovery from disease.

scholarly journals Successful Interference with Cellular Immune Responses to Immunogenic Proteins Encoded by Recombinant Viral Vectors

2001 ◽  
Vol 75 (1) ◽  
pp. 269-277 ◽  
Author(s):  
Adelaida Sarukhan ◽  
Sabine Camugli ◽  
Bernard Gjata ◽  
Harald von Boehmer ◽  
Olivier Danos ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Gene Transfer ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cellular Immune Responses ◽  
Cellular Immune

ABSTRACT Vectors derived from the adeno-associated virus (AAV) have been successfully used for the long-term expression of therapeutic genes in animal models and patients. One of the major advantages of these vectors is the absence of deleterious immune responses following gene transfer. However, AAV vectors, when used in vaccination studies, can result in efficient humoral and cellular responses against the transgene product. It is therefore important to understand the factors which influence the establishment of these immune responses in order to design safe and efficient procedures for AAV-based gene therapies. We have compared T-cell activation against a strongly immunogenic protein, the influenza virus hemagglutinin (HA), which is synthesized in skeletal muscle following gene transfer with an adenovirus (Ad) or an AAV vector. In both cases, cellular immune responses resulted in the elimination of transduced muscle fibers within 4 weeks. However, the kinetics of CD4+ T-cell activation were markedly delayed when AAV vectors were used. Upon recombinant Ad (rAd) gene transfer, T cells were activated both by direct transduction of dendritic cells and by cross-presentation of the transgene product, while upon rAAV gene transfer T cells were only activated by the latter mechanism. These results suggested that activation of the immune system by the transgene product following rAAV-mediated gene transfer might be easier to control than that following rAd-mediated gene transfer. Therefore, we tested protocols aimed at interfering with either antigen presentation by blocking the CD40/CD40L pathway or with the T-cell response by inducing transgene-specific tolerance. Long-term expression of the AAV-HA was achieved in both cases, whereas immune responses against Ad-HA could not be prevented. These data clearly underline the importance of understanding the mechanisms by which vector-encoded proteins are recognized by the immune system in order to specifically interfere with them and to achieve safe and stable gene transfer in clinical trials.

scholarly journals Mechanisms of T-Cell Activation by Human T-Cell Lymphotropic Virus Type I

1999 ◽  
Vol 63 (2) ◽  
pp. 308-333 ◽  
Author(s):  
Per Höllsberg
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Virus Type ◽  
High Frequency ◽  
Infected Host ◽  
Type I ◽  
Human T Cell ◽  
Cellular Immune System ◽  
Cellular Immune

SUMMARY The interactions between human T-cell lymphotropic virus type I (HTLV-I) and the cellular immune system can be divided into viral interference with functions of the infected host T cell and the subsequent interactions between the infected T cell and the cellular immune system. HTLV-I-mediated activation of the infected host T cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction pathways, cell cycle control, and apoptosis. These properties of Tax may well explain the ability of HTLV-I to immortalize T cells. It is not clear, though, how HTLV-I induces T-cell transformation (interleukin-2 [IL-2] independence). Recent evidence suggests that Tax may promote the G1- to S-phase transition, although this may involve additional proteins. A role for other viral proteins that may constitutively activate the IL-2 receptor pathway has also been suggested. By virtue of their activated state, HTLV-I-infected T cells can nonspecifically activate resting, uninfected T cells via virus-mediated upregulation of adhesion molecules. This may favor viral dissemination. Moreover, the induction of a remarkably high frequency of antiviral CD8+ T cells does not appear to eliminate the infection. Indeed, individuals with a high frequency of virus-specific CD8+ T cells have a high viral load, indicating a state of chronic immune system stimulation. Thus, while an activated immune system is needed to eradicate the infection, the spread of the HTLV-I is also accelerated under these conditions. A detailed knowledge of the molecular interactions between virus-specific CD8+ T cells and immunodominant viral epitopes holds promise for the development of specific antiviral therapy.

A glimpse into the diverse cellular immunity against SARS-CoV-2

2021 ◽  
Author(s):  
Cheng-Wei Chang ◽  
Yuchen Liu ◽  
Cheng Jiao ◽  
Hongwei Liu ◽  
Xiaochuan Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Antibody Response ◽  
Cellular Immunity ◽  
Viral Antigens ◽  
Cellular Immune

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific cellular immune response may prove to be essential for long-term immune protection against the novel coronavirus disease 2019 (COVID-19). To assess COVID-19-specific immunity in the population, we synthesized selected peptide pools of SARS-CoV-2 structural and functional proteins, including Spike (S), Membrane (M), Envelope (E), Nucleocapsid (N) and Protease (P) as target antigens. Survey of the T cell precursur frequencies in healthy individuals specific to these viral antigens demonstrated a diverse cellular immunity, including high, medium, low and no responders. This was further confirmed by in vitro induction of anti-SARS-CoV-2 T cell immune responses using dendritic cell (DC)/T cell coculture, which supported the corresponding T cell precursor frequencies in each of the individuals tested. In general, the combination of all five viral antigen pools induced the strongest cellular immune response, yet individual donors responded differently to different viral antigens. Importantly, in vitro restimulation of the T cells with the DC-peptides induced increased anti-viral immune responses in all individuals even in the no responders, suggesting that repeated antigen stimulation could elicit a broad protection in immune naïve population. Our analysis recapitulates the critical role of cellular immunity in fighting COVID-19 and the importance of analyzing anti-SARS-CoV-2 T cell response in addition to antibody response in the population.ImportanceFacing the rapid evolving SARS-CoV-2 variants in the world, current emphasis on antibody-producing vaccines needs a quick revisit. The virus-specific cellular immunity may prove to be essential for long-term protection against COVID-19. This study designed a series of antigenic peptides encompassing the conserved and/or essential domains of Spike (S), Membrane (M), envelope (E), Nucleocapsid (N) and Protease (P) as targets to assess Covid-19-specific immunity in the population. The results demonstrated a diverse cellular immunity, including high, medium, low and no responders. This was verified by in vitro generation of anti-SARS-CoV-2 T-cells from these subjects. The study suggested that individuals responded differently to the different viral antigens, and importantly, repeated stimulation could produce virus specific T cells in all individuals, including the no responders. This study illustrates the needs for assessing anti-viral cellular immunity in addition to antibody response in the general population.

scholarly journals P01.13 MERTK signaling is critical for T cell proliferation and memory

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A14.2-A15
Author(s):  
RM Powell ◽  
MJW Peeters ◽  
A Rachbech ◽  
PT Straten
Keyword(s):  
T Cells ◽  
Cell Division ◽  
T Cell ◽  
Cd8 T Cells ◽  
Central Memory ◽  
T Cell Proliferation ◽  
Flow Cytometric ◽  
Donor T Cells ◽  
Memory Differentiation

BackgroundOverexpression of TAM receptors, including MERTK, in some cancers are integral for chemoresistance, proliferation and metastasis.1 Our group has previously demonstrated that T cells also express MERTK and engagement of MERTK signaling is responsible for increased proliferation, functional capacity and metabolic fitness.2 It is therefore important to further study the effect of MERTK inhibition on T cell function in the context of cancer treatments where MERTK inhibitors may play a role. Here we provide evidence that MERTK inhibition impacts greatly on T cell proliferation, specifically reducing phosphorylated mTOR. We have also demonstrated that MERTK expression is increased on CD8 central memory subsets during longterm expansion providing evidence that this signaling pathway may be important for sustaining T memory responses.Materials and MethodsFlow cytometric analysis was used to investigate the effect of titration of MERTK small molecule inhibitor UNC2025 on healthy donor T cells activated with CD3/CD28 dynabeads. Cell trace dye was used to track proliferation of CD4 and CD8 T cells along with markers of memory differentiation (CCR7 and CD45RO), activation (CD137) and function (IFNy, Tnfa and IL-2). MERTK signaling was assessed using phospho flow cytometric methodology of phosphorylated mTOR, AKT, ERK1/2, p38-MAPK and STAT5. Long term cultures of donor T cells of up to 28 days were investigated for MERTK expression alongside memory differentiation.ResultsWe demonstrated that moderate concentrations of MERTK inhibitor reduced proliferation of activated T cells. Despite inhibition of cell division, cell size still increased 2 fold compared to resting cells and cell viability remained unchanged. Additionally, the proportion of central memory to effector memory populations and intracellular cytokine production was not impacted. Analysis of molecules involved in MERTK signaling revealed that phosphorylated mTOR was significantly modulated following the addition of MERTK inhibitor. Long term culture of CD8 T cells demonstrated MERTK was significantly increased following early and late re-stimulation, and expression of MERTK was strongly associated with central memory subsets.ConclusionsOur results demonstrate that inhibition of MERTK signaling on T cells reduces cell division where mTOR is significantly impacted. Despite this, other functional aspects, such as intracellular cytokine production remain unchanged. Therefore, interruption of MERTK signaling on T cells has a specific effect on cell division rather than cytotoxic function on a cell by cell basis. This has potential ramifications on the use of MERTK inhibitors to treat tumors where the ability to form substantial cytotoxic T cell populations might be reduced. In addition, increased MERTK expression on central memory subsets during long term culture suggests this signaling pathway could be critical for generating memory pools of T cells and provide new avenues for the improvement of adoptive T cell therapy protocols.ReferencesCummings CT, Deryckere D, Earp HS, Graham DK. Molecular pathways: MERTK signaling in cancer. Clin Cancer Res 2013;19(19):5275–5280.Peeters MJW, Dulkeviciute D, Draghi A, et al. MERTK Acts as a Costimulatory Receptor on Human CD8+T Cells. Cancer Immunol Res 2019;7(9):1472–1484.Disclosure InformationR.M. Powell: None. M.J.W. Peeters: None. A. Rachbech: None. P.T. Straten: None.

PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4671-4678 ◽  
Author(s):  
Ji-Yuan Zhang ◽  
Zheng Zhang ◽  
Xicheng Wang ◽  
Jun-Liang Fu ◽  
Jinxia Yao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Specific Memory ◽  
Memory Cd8 T Cell

Abstract The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8+ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-γ production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8+ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs.

Reconstitution of the T Cell Repertoire Following Treatment with Alemtuzumab in Patients with B-Cell Chronic Lymphocytic Leukemia (B-CLL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2986-2986
Author(s):  
Mohammad R. Rezvany ◽  
Mahmood J. Tehrani ◽  
Claes Karlsson ◽  
Jeanette Lundin ◽  
Hodjattallah Rabbani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Long Term Follow Up

Abstract Background and Methods: B-cell chronic lymphocytic leukemia (B-CLL) occurs as a result of clonal accumulation of functionally abnormal B cells. Alemtuzumab is a humanized monoclonal antibody specific for the CD52 antigen, which is highly expressed on both B-CLL cells and normal lymphocytes, but not on hematopoietic (CD34) stem cells. Alemtuzumab has been shown to effectively deplete the blood and bone marrow of lymphocytes, including CD4 and CD8 T cells, which may lead to profound immunosuppression and make patients more susceptible to infections. We and others have previously shown that the CD4 T cells in B-CLL patients may be clonally distinct from the normal population in that they present a more clonal pattern of the T-cell receptor (TCR) repertoire (Rezvany et al, Blood2003;101:1063–1070). It is therefore of interest to study the T cell repertoire following alemtuzumab administration as well as factors affecting T cell reconstitution following CD52 targeted therapy. In this study, we evaluated in depth the T-cell receptor-beta-variable sequence (TCR BV) in CD4 and CD8 T cells by real-time PCR, before and repeatedly after/during long term follow-up, in 5 B-CLL patients who had received alemtuzumab as first-line therapy (Lundin et al, Blood2002;100:768–773). Also, an analysis was conducted of CDR3 length polymorphism to describe changes in the clonality pattern. Results: A decline in most of BV genes either in CD4 or CD8 T cells was observed shortly after alemtuzumab treatment, which was followed by a gradual increase in most of the BV genes during long-term follow up. CDR3 length polymorphism analysis shortly after treatment revealed an even more highly restricted pattern in CD4 T cells compared to baseline with a shift towards a monoclonal/oligoclonal pattern regardless of increased or decreased BV usage. Furthermore, in the analysis of the clonal spectrum that was expressed shortly after alemtuzumab therapy, the number of peaks was significantly reduced in CD4 (P <0.01) but not in CD8 T cells, which was followed by a gradual increase in diversity towards a polyclonal repertoire during long-term follow up. Conclusions: These results indicate that perturbations in the T cell repertoire following alemtuzumab are complex, and are not reflected by changes in CD4/CD8 T cell numbers only. The restricted CDR3 pattern present prior to therapy became even more restricted after end of treatment, followed by a normalization of CDR3 patterns in CD4 T-cells during long-term follow-up. These results further suggest a regulatory role for T cells in relation to the malignant B cell clone in patients with B-CLL.

Therapeutic Anti-Tumor Immunity Mediated by Transiently Engrafting Allogeneic Lymphocytes: The “Allogeneic Effect” Revisited.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5255-5255
Author(s):  
Heather J. Symons ◽  
M. Yair Levy ◽  
Jie Wang ◽  
Xiaotao Zhou ◽  
Ephraim J. Fuchs
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Host Immune System ◽  
Tumoricidal Activity ◽  
Tumor Bearing ◽  
Anti Tumor Activity ◽  
Allogeneic Lymphocytes

Abstract The “allogeneic effect” refers to the induction of host B cell antibody synthesis or host T cell cytotoxicity, including tumoricidal activity, by an infusion of allogeneic lymphocytes. We have previously shown that treatment of mice with cyclophosphamide (Cy) followed by infusion of CD8+ T cell-depleted allogeneic spleen cells (Cy + CD8− DLI) induces anti-tumor activity in a model of minimal residual leukemia, even though the donor cells are eventually rejected by the host immune system. The purpose of the current investigation was to test the activity of Cy + CD8− DLI in the treatment of well-established cancer, and to characterize the mechanisms of the anti-tumor effect. BALB/c mice were inoculated intravenously (IV) with the syngeneic A20 lymphoma/leukemia or the RENCA renal cell carcinoma on day 0 and were then treated with nothing, Cy alone on day 14, or Cy + CD8− DLI from MHC-mismatched C57BL/6 donors on day 15. In both tumor models, the combination of Cy + CD8− DLI significantly prolonged survival compared to mice treated with nothing or with Cy alone. While depletion of CD4+ T cells from the DLI significantly diminished the beneficial effect of CD8− DLI, purified CD4+ T cells alone were inactive, demonstrating that donor CD4+ T cells and another population of cells were required for optimal anti-tumor activity. Several observations pointed to an active role for the host immune system in the anti-tumor activity of Cy + CD8− DLI. First, host T cells participated in the anti-tumor effect of treatment with Cy alone, since the drug’s activity was diminished in tumor-bearing scid mice or in normal BALB/c mice depleted of T cells. Second, while Cy + CD8− DLI caused no GVHD in tumor-bearing but immunocompetent BALB/c recipients, it caused fatal acute GVHD in either tumor-bearing scid or T-cell depleted BALB/c mice. Finally, the anti-tumor effect of Cy + CD8- DLI was also significantly inhibited in BALB/c mice that were depleted of CD8+ T cells. These results demonstrate that transiently engrafting T cells administered after Cy can induce significant anti-tumor effects against both solid and liquid tumors. We propose that upon recognition of alloantigen on host antigen-presenting cells (APCs), allogeneic donor CD4+ T cells deliver activating ligands to the APCs, thereby generating effective “help” to break tolerance in tumor-specific host CD8+ T cells. This mechanism may correspond to the “allogeneic effect” in the anti-tumor response described over three decades ago.

Open-Label Study of Cellular Immunity in Dialysis Patients after Intravenous Ibandronate.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3901-3901
Author(s):  
Raoul Bergner ◽  
Burkhard Weiss ◽  
Martin Hoffman ◽  
Dirk Henrich ◽  
Michael Uppenkamp
Keyword(s):  
Immune System ◽  
Acute Phase ◽  
Rejection Rate ◽  
Phase Reaction ◽  
Transplant Recipients ◽  
Dialysis Patients ◽  
Open Label ◽  
Cellular Immune System ◽  
Cellular Immune

Abstract Intravenous infusion of bisphosphonates can cause acute phase reactions which may be caused by changes in the cellular immune system, particularly in lymphocyte subtypes. These immune changes and an acute phase reaction both normally disappear after 48 hours. Previous studies have shown that kidney transplant recipients treated with immunosuppressive therapy and ibandronate for bone protection have a lower rejection rate than those treated with immunosuppressive therapy and placebo.1 This suggests that there may be long-term changes in the immune system occurring with ibandronate treatment. We investigated the long term changes in the cellular immune system during ibandronate treatment in dialysis patients. As these patients are not normally treated with immunosuppressive or cytotoxic agents, which can cause changes in the cellular immune system, they are an eligible population for such a study. In this open-label trial, 16 patients with end-stage renal disease receiving regular hemodialysis were recruited. All patients were treated with ibandronate 2mg every 4 weeks for renal osteopathy; a dose that provides similar AUC and bone exposure as a 6mg dose in patients with normal renal function. The cellular immune system was investigated before first ibandronate application and the measurement was repeated at weeks 2, 4 and 48. The following parameters were measured by blood count differentiation: leucocytes, granulocytes lymphocytes, monocytes. Lymphocyte subtypes were measured by flow cytometry: B-lymphocytes (CD3+/CD19+), T-helper cells (CD3+/CD4+), T-suppressor cells (CD3+/CD8+), natural killer (NK)-cells (CD3+/CD16+56+), helper-inducer cells (CD4+/CD29+), activated T-cells (CD3+/HLA-DR+), activated T-lymphocytes (CD3+/CD25+), naive T-cells (CD3+/CD45RA+) and memory-T-lymphocytes (CD3+/CD45RO+). Twelve patients completed the study and were evaluated. One patient dropped out because of flu-like symptoms with muscle pain after the first ibandronate infusion; however this was well controlled with paracetamol. Three patients died due to concomitant diseases (diabetes and cardiovascular events). There were no statistically significant differences in cellular immunity over time as measured in weeks 0, 2, 4 and 48 (see Figure). In this small-pilot study of dialysis patients receiving ibandronate, no changes in the cellular immune system were observed over time. Changes in different lymphocyte subtypes, which occur in the acute phase reaction after first infusion, were not seen. Reduced rejection rate in transplant recipients after ibandronate infusion cannot be explained by changes in the cellular immune system, and must therefore occur by another mechanism. Figure Figure

The Role of Bone Marrow T Cells in Regulating Hematopoietic Stem Cell Function.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2349-2349
Author(s):  
Claudia Brandao ◽  
Alexander M. de Bruin ◽  
Martijn A. Nolte
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cd8 T Cells ◽  
Feedback Mechanism ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 2349 After immune activation, effector/memory T cells, including virus-specific CD8 T cells, are known to migrate to the bone marrow (BM), where they can be maintained by the production of IL-15 by the stroma; however, it is not yet known whether these T cells also have a function at this site. Since depletion of T cells from allogenic BM grafts compromises HSC engraftment, we hypothesize that T cells can directly influence the balance between differentiation and self-renewal of hematopoietic stem cells (HSCs). To test the ability of T cells to affect hematopoiesis, we performed co-cultures of HSCs and T cells isolated from murine BM. We found that T cells localized in the BM are able to enhance HSC differentiation as well as their self-renewal capacity. This feature is specific for BM central memory (CM) CD8 T cells, since other T cell subsets are not able to affect HSCs to the same extent. Moreover, depletion of CM CD8 T cells from the total BM T cell pool abrogates the impact on HSC differentiation and self-renewal, indicating that this particular T cell population is both sufficient and required for the observed effects. BM CM CD8 T cells do not affect quiescence of HSCs, but do enhance their proliferative capacity, and we found that supernatant from CM CD8 T cells is sufficient for this effect. Interestingly, competitive transplantation assays showed that HSCs cultured with CM CD8 T cells-derived supernatant contribute much better to leukocyte formation than medium-treated HSCs. This effect is seen in both the myeloid and lymphoid compartment, indicating that CM CD8 T cells are able to release soluble factors that support and enhance the multilineage reconstitution capacity of HSCs. Functional studies with blocking antibodies or knock-out mice showed that the supernatant-mediated effect is not caused by the hematopoietic cytokines IL3, IL6, IL21, GM-CSF, RANTES, TNFα or IFNγ. Preliminary data indicate that this feedback mechanism of the immune system on the hematopoietic process in the bone marrow is also present in the human situation, since autologous BM T cells increase the numbers of human HSCs, as well as their differentiation capacity. Overall, these findings demonstrate that T cells have an important function in the BM and that especially CD8 TCM cells can directly influence HSC homeostasis. We postulate that this feedback mechanism of the immune system on the hematopoietic process in the BM is particularly relevant during viral infection, as the efficient migration of virus-specific CD8 T cells to the BM could well benefit the replenishment of the HSC/progenitor cell compartment and restoration of blood cell numbers that got lost upon infection. Disclosures: No relevant conflicts of interest to declare.

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