scholarly journals Conventional CD4+CD25- and Regulatory CDCD4+25+ t Cells Have Opposite Effects on Progenitor Cells and Hematopoietic Reconstitution Following Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 654-654
Author(s):  
Antonia MS Mueller ◽  
Jessica Poyser ◽  
Holbrook E Kohrt ◽  
Judith A Shizuru
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Immune Cells ◽  
T Cell Subsets ◽  
Mixed Chimerism ◽  
Allogeneic Hct ◽  
Hematopoietic Reconstitution

Abstract The bone marrow (BM) is a complex microsystem to support lifelong blood production. At steady-state most hematopoietic stem cells (HSC) are quiescent. However, in situations of increased demand, their activation is triggered by an array of signals, such as cytokines. Following hematopoietic cell transplantation (HCT) in the phase of hematopoietic reconstitution maximal blood production is needed. In an HCT donor HSC are given together with immune cells in the belief that T cells support HSC engraftment and regeneration of the blood system. Yet, states of immune mediated BM insufficiency, hypoplasia, and cytopenias are often observed. Moreover, with increased use of reduced intensity conditioning (RIC) engraftment failure has reemerged as a serious problem. Here, we studied the effects of distinct T cell subsets on hematopoietic reconstitution following HCT; specifically, we examined how conventional CD4+CD25- T cells (CD4conv) vs regulatory T cells (CD4+CD25+, Treg) modify the BM environment and influence donor-HSC activity and engraftment. We used minor-mismatched mouse models, non-myeloablative total body irradiation (TBI) conditioning and transplantations of purified HSC (KTLS; cKit+Thy1.1loLin–Sca-1+) plus selected T cell subsets. Recipients of HSC, HSC+Treg or HSC+CD8+ - but not HSC+CD4conv- demonstrated prompt donor engraftment with mixed chimerism in all lineages. Transplantation of HSC+Treg resulted in significantly faster lymphocyte recovery and higher levels of donor chimerism compared with recipients of HSC, HSC+CD8+ or HSC+CD4conv. Particularly B-cell regeneration was markedly higher in HSC+Treg-recipients compared with all other groups. In contrast, (B-) lymphopoiesis was severely impaired in recipients of HSC+CD4conv; when lymphocytes recovered eventually they were of host type. Moreover, in BM and spleens of HSC+CD4conv recipients pronounced hypocellularity was observed. This suppression of hematopoiesis was due to IFNg secretion of donor CD4conv cells, which were activated by dendritic cells via IL-12. High cytokine levels (of both IL-12 and IFNg) were only detectable in the BM (and not the spleen) of HSC+CD4conv recipients, where they resulted in an arrest of early hematopoiesis at the stage of short-term HSC and decreased cell-cycle activity within the progenitor compartment. As a consequence more mature multipotent progenitors were lacking. The key role of IFNg in halting hematopoietic maturation was confirmed by using CD4conv cells from IFNg-/- mice, which had no suppressive effects on BM cellularity and maturation of blood cells; rather, recipients of HSC+IFNg-/-CD4conv cells had equivalent cell numbers and subset distributions as mice given HSC alone. We hypothesized that differences of hematopoietic regeneration and donor engraftment relate to cell cycle activity of HSC in presence of CD4conv vs Tregs. To study the influence of these CD4-subsets on HSC cycling in more detail FACS-purified Treg vs CD4conv cells were infused into congenic mice following low-dose TBI-stimulation. In fact, on d+8 post-infusion HSC in the BM of Treg-recipients had increased cell-cycling activity in long-term-HSC and multipotent-progenitor fractions compared with mice given CD4conv cells or radiation only. These data lead us to speculate that Tregs promote, directly or indirectly, HSC proliferation; in the context of an allogeneic HCT this increased cycling of host HSC my open-up the niche space required to allow donor HSC to engraft. In contrast, CD4convinhibited HSC cycling activity, resulting in BM hypoplasia and cytopenias; at the same time donor HSC engraftment was impaired due to HSC-niche occupation by quiescent host HSC. Our findings underscore the critical role of T cells in regulating hematopoiesis under physiologic conditions and even more following allogeneic HCT. While donor T cells are generally believed to improve regeneration of the blood post-HCT and to be required to overcome host barriers, our data suggest Treg facilitate engraftment and hematopoiesis by increasing HSC cycling-activity and thereby making marrow sites available. CD4conv appear to have the opposite effect, resulting in decreased HSC proliferation and maturation - thus occupation of HSC niches. Our studies are of particular relevance to allogeneic HCT settings using RIC, where host HSC persist and grafts can be rejected by residual host immune cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Alterations of Peripheral Blood T Cell Subsets following Donor Lymphocyte Infusion in Patients after Allogeneic Stem Cell Transplantation

Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 692-702
Author(s):  
Ann-Kristin Schmaelter ◽  
Johanna Waidhauser ◽  
Dina Kaiser ◽  
Tatjana Lenskaja ◽  
Stefanie Gruetzner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Donor Lymphocyte Infusion ◽  
T Cell Subsets ◽  
Mixed Chimerism

Donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) is an established method to enhance the Graft-versus-Leukemia (GvL) effect. However, alterations of cellular subsets in the peripheral blood of DLI recipients have not been studied. We investigated the changes in lymphocyte subpopulations in 16 patients receiving DLI after successful alloSCT. Up to three DLIs were applied in escalating doses, prophylactically for relapse prevention in high-risk disease (n = 5), preemptively for mixed chimerism and/or a molecular relapse/persistence (n = 8), or as part of treatment for hematological relapse (n = 3). We used immunophenotyping to measure the absolute numbers of CD4+, CD8+, NK, and CD56+ T cells and their respective subsets in patients’ peripheral blood one day before DLI (d-1) and compared the results at day + 1 and + 7 post DLI to the values before DLI. After the administration of 1 × 106 CD3+ cells/kg body weight, we observed an overall increase in the CD8+ and CD56+ T cell counts. We determined significant changes between day − 1 compared to day + 1 and day + 7 in memory and activated CD8+ subsets and CD56+ T cells. Applying a higher dose of DLI (5 × 106 CD3+ cells/kg) led to a significant increase in the overall counts and subsets of CD8+, CD4+, and NK cells. In conclusion, serial immune phenotyping in the peripheral blood of DLI recipients revealed significant changes in immune effector cells, in particular for various CD8+ T cell subtypes, indicating proliferation and differentiation.

scholarly journals The role of unconventional T cells in COVID-19

2021 ◽  
Author(s):  
Kristen Orumaa ◽  
Margaret R. Dunne
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Treatment Strategies ◽  
Γδ T Cells ◽  
Protective Role ◽  
T Cell Subsets ◽  
Viral Immunity ◽  
Mait Cells

AbstractCOVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.

scholarly journals The impact of body mass index on adaptive immune cells in the human bone marrow

2020 ◽  
Author(s):  
Luca Pangrazzi ◽  
Erin Naismith ◽  
Carina Miggitsch ◽  
Jose’ Antonio Carmona Arana ◽  
Michael Keller ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Cells ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Abstract Background. Obesity has been associated with chronic inflammation and oxidative stress. Both conditions play a determinant role in the pathogenesis of age-related diseases, such as immunosenescence. Adipose tissue can modulate the function of the immune system with the secretion of molecules influencing the phenotype of immune cells. The importance of the bone marrow (BM) in the maintenance of antigen-experienced adaptive immune cells has been documented in mice. Recently, some groups have investigated the survival of effector/memory T cells in the human BM. Despite this, whether high body mass index (BMI) may affect immune cells in the BM and the production of molecules supporting the maintenance of these cells it is unknown.Methods. Using flow cytometry, the frequency and the phenotype of immune cell populations were measured in paired BM and PB samples obtained from persons with different BMI. Furthermore, the expression of BM cytokines was assessed. The influence of cytomegalovirus (CMV) on T cell subsets was additionally considered, dividing the donors into the CMV- and CMV+ groups.Results. Our study suggests that increased BMI may affect both the maintenance and the phenotype of adaptive immune cells in the BM. While the BM levels of IL-15 and IL-6, supporting the survival of highly differentiated T cells, and oxygen radicals increased in overweight persons, the production of IFNγ and TNF by CD8+ T cells was reduced. In addition, the frequency of B cells and CD4+ T cells positively correlated with BMI in the BM of CMV- persons. Finally, the frequency of several T cell subsets, and the expression of senescence/exhaustion markers within these subpopulations, were affected by BMI. In particular, the levels of bona fide memory T cells may be reduced in overweight persons.Conclusion. Our work suggests that, in addition to aging and CMV, obesity may represent an additional risk factor for immunosenescence in adaptive immune cells. Metabolic interventions may help in improving the fitness of the immune system in the elderly.

Body mass index affects adaptive immune cells in the human bone marrow

2020 ◽  
Author(s):  
Luca Pangrazzi ◽  
Erin Naismith ◽  
Carina Miggitsch ◽  
Jose’ Antonio Carmona Arana ◽  
Michael Keller ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Body Mass ◽  
Immune Cells ◽  
T Cell Subsets ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Abstract Background. Obesity has been associated with chronic inflammation and oxidative stress. Both conditions play a determinant role in the pathogenesis of age-related diseases, such as immunosenescence. Adipose tissue can modulate the function of the immune system with the secretion of molecules influencing the phenotype of immune cells. Recently, the importance of the bone marrow (BM) in the maintenance of antigen-experienced adaptive immune cells has been documented. Despite this, whether high body mass index (BMI) may affect immune cells in the BM and the production of molecules supporting the maintenance of these cells it is unknown. Methods. Using flow cytometry, the frequency and the phenotype of immune cell populations were measured in paired BM and PB samples obtained from persons with different BMI. Furthermore, the expression of BM cytokines was assessed. The influence of cytomegalovirus (CMV) on T cell subsets was additionally considered, dividing the donors into the CMV - and CMV + groups. Results. Our study suggests that increased BMI may affect both the maintenance and the phenotype of adaptive immune cells in the BM. While the BM levels of IL-15 and IL-6, supporting the survival of highly differentiated T cells, and oxygen radicals increased in overweight persons, the production of IFNγ and TNF by CD8 + T cells was reduced. In addition, the frequency of B cells and CD4 + T cells positively correlated with BMI in the BM of CMV - persons. Finally, the frequency of several T cell subsets, and the expression of senescence/exhaustion markers within these subpopulations, were affected by BMI. In particular, the levels of bona fide memory T cells may be reduced in overweight persons. Conclusion. Our work suggests that obesity may represent an independent risk factor supporting immunosenescence, in addition to aging and CMV. Metabolic interventions may help in improving the fitness of the immune system in the elderly.

scholarly journals Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1974 ◽  
Author(s):  
Linde Dekker ◽  
Coco de Koning ◽  
Caroline Lindemans ◽  
Stefan Nierkens
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cell Subset ◽  
Γδ T Cells ◽  
Hematopoietic Cell ◽  
T Cell Subsets ◽  
T Cell Subset

Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes.

scholarly journals Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Guohe Song ◽  
Yang Shi ◽  
Meiying Zhang ◽  
Shyamal Goswami ◽  
Saifullah Afridi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
T Cell Subsets ◽  
M2 Macrophage ◽  
Advanced Hcc ◽  
Immune Cell Subsets

AbstractDiverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.

scholarly journals Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

2011 ◽  
Vol 208 (5) ◽  
pp. 1069-1082 ◽  
Author(s):  
Daigo Hashimoto ◽  
Andrew Chow ◽  
Melanie Greter ◽  
Yvonne Saenger ◽  
Wing-Hong Kwan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Expansion ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Host Macrophage

Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

Proportions of T-Cell CD8+ Subsets Lacking CD28 Expression at Day 30 after Myeloablative Allogeneic Stem Cell Transplantation Are Predictive for Relapse and Chronic GVHD.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2979-2979
Author(s):  
Ibrahim Yakoub-Agha ◽  
Pasquine Saule ◽  
Leonardo Magro ◽  
Pascale Cracco ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Mixed Chimerism ◽  
Effector Memory ◽  
Myeloablative Conditioning ◽  
Risk Of Relapse

Abstract The curative potential of allo-SCT for malignancies derives from the progressive reconstitution of the immune system and the development of effective anti-tumor immunity, but GVHD and disease relapse remain considerable obstacles to improvement in overall outcomes. Because in recipients target antigens are persisting, donor-derived T-cell responses may be expected to lead to the accumulation of a sizable proportion of differentiated T-cells, as happens following infection with persisting pathogens. A few cross-sectional studies have pointed to the preponderance of certain memory T-cell subsets associated with chronic GVHD (cGVHD), but the subset identified differed between studies. Inasmuch as qualitative T-cell recovery takes months to years to complete and there is substantial variability in time to development of GVHD or relapse, serial analysis might be more suitable to unveil early changes in T-cell subset composition attributable to transplantation-related events. From October 2003 on, 55 pts who underwent an allo-SCT after myeloablative conditioning were monitored prospectively in terms of clinical post-graft complications, including graft rejection, infections, GVHD and relapse. Blood samples were obtained on days 30±2, 60±3, 90±5, 180±10 and 365±15 post-transplant. Naive (CD45RA+CCR7+), central memory (TCM, CD45RAnegCCR7+), effector memory (TEM, CD45RAnegCCR7neg), and terminally differentiated effector (TTD, CD45RA+CCR7neg) were enumerated within the CD4+ and CD8+ pools, and the percentage of cells coexpressing CD28 was calculated within each eight subsets. The degree of donor-derived T-cell chimerism was assessed by real time PCR (sensitivity ≤ 1%). Median follow-up was 733 d (404–1251). Dynamics of CD4+ and CD8+ naive, TCM, TEM, and TTD were similar between the pts who developed cGVHD (n=15) and those who did not and between pts who relapsed and those who did not. However, costaining to detect CD28 demonstrated contrasting differences between cGVHD and relapse. At day 30, pts who subsequently relapsed (n=17) had elevated percentages of cells keeping CD28 expression within CD8+ T-cell subsets (TCM, p=.001; TCM, p=.021; and TTD, p=.007). Conversely, pts who subsequently developed cGVHD (n=15; only one relapsed) had diminished percentages of CD28+ cells within the two CD8+CCR7+ subsets at day 30 (p=.002 and p=.034, respectively). Loss of CD28 expression is known to be a hallmark of CMV infection but multivariate analysis ruled out, however, a confounding effect of CMV. Adjusted hazard ratios were 0.10 (95% CI, 0.01-0.76; p=.026) and 5.56 (95% CI, 1.16-25.00; p=.032) with CD28neg cells 16.7% of all CD8+ TCM at day 30 for relapse and cGVHD, respectively. Furthermore, pts with relapse had more often mixed chimerism at day 30 while those with cGVHD had more often full-donor chimerism (p=.042 and p=.023, respectively). CONCLUSION: This prospective study is the first to associate an early contrasting change in CD8+CD28neg T-cells with the risk of relapse and cGVHD after a myeloablative conditioning. Determination at day 30 of the proportions of CD8+ T-cell subsets expressing CD28 and of the level of T-cell chimerism could assist in predicting risk of relapse and cGVHD and help build an algorithm for the management of immunosuppressive treatment.

scholarly journals A possible role of immunopathogenesis in COVID-19 progression

2020 ◽  
Author(s):  
Moritz Anft ◽  
Krystallenia Paniskaki ◽  
Arturo Blazquez-Navarro ◽  
Adrian Doevelaar ◽  
Felix S. Seibert ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Humoral Immunity ◽  
Viral Infections ◽  
Cell Subset ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Clear Correlation

AbstractBackgroundThe efficacy of the humoral and cellular immunity determines the outcome of viral infections. An appropriate immune response mediates protection, whereas an overwhelming immune response has been associated with immune-mediated pathogenesis in viral infections. The current study explored the general and SARS-CoV-2 specific cellular and humoral immune status in patients with different COVID-19 severities.MethodsIn this prospective study, we included 53 patients with moderate, severe, and critical COVID-19 manifestations comparing their quantitative, phenotypic, and functional characteristics of circulating immune cells, SARS-CoV-2 antigen specific T-cells, and humoral immunity.ResultsSignificantly diminished frequencies of CD8+T-cells, CD4+ and CD8+T-cell subsets with activated differentiated memory/effector phenotype and migratory capacity were found in circulation in patients with severe and/or critical COVID-19 as compared to patients with moderate disease. Importantly, the improvement of the clinical courses from severe to moderate was accompanied by an improvement in the T-cell subset alterations. Furthermore, we surprisingly observed a detectable SARS-CoV-2-reactive T-cell response in all three groups after stimulation with SARS-CoV-2 S-protein overlapping peptide pool already at the first visit. Of note, patients with a critical COVID-19 demonstrated a stronger response of SARS-CoV-2-reactive T-cells producing Th1 associated inflammatory cytokines. Furthermore, clear correlation between antibody titers and SARS-CoV-2-reactive CD4+ frequencies underscore the role of specific immunity in disease progression.ConclusionOur data demonstrate that depletion of activated memory phenotype circulating T-cells and a strong SARS-CoV-2-specific cellular and humoral immunity are associated with COVID-19 disease severity. This counter-intuitive finding may have important implications for diagnostic, therapeutic and prophylactic COVID-19 management.

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