Hemophagocytic lymphohistiocytosis (HLH) and related disorders

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 127-131 ◽  
Author(s):  
Alexandra H. Filipovich
Keyword(s):  
T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Hematopoietic Cell Transplantation ◽  
Viral Infections ◽  
Clinical Findings ◽  
Antiinflammatory Therapy ◽  
Genetic Causes ◽  
Life Threatening ◽  
Genetically Determined ◽  
Antigen Presenting

Abstract Hemophagocytic lymphohistiocytosis (HLH), which has many genetic causes, is characterized by multi-system inflammation. HLH is a reactive process resulting from prolonged and excessive activation of antigen presenting cells (macrophages, histiocytes) and CD8+ T cells. Hemophagocytosis, which is mediated through the CD163 heme-scavenging receptor, is a hallmark of activated macrophages/histiocytes and is the characteristic finding for which the disorder was named. The majority of genetic causes identified to date affect the cytotoxic function of NK and T cells, crippling immunologic mechanisms that mediate natural immune contraction. The predominant clinical findings of HLH are fevers (often hectic and persistent), cytopenias, hepatitis and splenomegaly. Due to the life-threatening implications of the diagnosis of genetically determined HLH, antiinflammatory therapy, often consisting of steroids, etoposide or antithymocyte globulin (ATG), should be instituted promptly, followed by curative hematopoietic cell transplantation. Secondary HLH, associated with autoimmune disorders or viral infections in teens and adults, also carries a significant mortality rate and should be managed in consultation with specialists familiar with the diagnosis and treatment of such disorders.

scholarly journals Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4440-4448 ◽  
Author(s):  
Arnab Ghosh ◽  
Wolfgang Koestner ◽  
Martin Hapke ◽  
Verena Schlaphoff ◽  
Florian Länger ◽  
...  
Keyword(s):  
T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Leukemia Cell ◽  
Donor Lymphocyte Infusion ◽  
Graft Versus Leukemia ◽  
Life Threatening ◽  
Host Origin ◽  
Antigen Presenting

Abstract Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cells (ETCs) mediate anti-leukemia effects only when primed on recipient-derived APCs. Loading of APCs in vitro with leukemia cell lysate, chimerism status of the recipient, and timing of adoptive transfer after HCT are important factors determining the outcome. Delayed transfer of ETCs resulted in strong GVL effects in leukemia-bearing full chimera (FC) and mixed chimera (MC) recipients, which were comparable with the GVL/GVHD rates observed after the transfer of naive donor lymphocyte infusion (DLI). Upon early transfer, GVL effects were more pronounced with ETCs but at the expense of significant GVHD. The degree of GVHD was most severe in MCs after transfer of ETCs that had been in vitro primed either on nonpulsed recipient-derived APCs or with donor-derived APCs.

scholarly journals Nivolumab treatment of relapsed/refractory Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis in adults

Blood ◽  
2020 ◽  
Vol 135 (11) ◽  
pp. 826-833 ◽  
Author(s):  
Pengpeng Liu ◽  
Xiangyu Pan ◽  
Chong Chen ◽  
Ting Niu ◽  
Xiao Shuai ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Epstein Barr Virus ◽  
Sequencing Analysis ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Life Threatening ◽  
Programmed Death Protein 1 ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median follow-up of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1–positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.

Hemophagocytic Lymphohistiocytosis: Update of Biology and Treatment Options

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-9-SCI-9
Author(s):  
Alexandra H. Filipovich
Keyword(s):  
T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Autosomal Recessive ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Clinical Signs ◽  
The United States ◽  
Activated T Cells ◽  
High Incidence

Abstract Abstract SCI-9 Hemophagocytic lymphohistiocytosis (HLH) is a group of immunodeficiencies characterized by clinical signs and symptoms of extreme inflammation. HLH is now more widely recognized and no longer viewed as a disorder of young children only, as more adults are being diagnosed and treated. HLH is defined by a unique pattern of clinical findings. In addition to fevers, cytopenias, hepatitis, and splenomegaly, markedly increased levels of inflammatory markers in the blood (ferritin and sCD163 reflecting activation of antigen presenting cells; sIL2Ra and neopterin reflecting activation of T cells) constitute the collection of diagnostic criteria. Activation of inflammatory cells within the central nervous system (CNS) is found in approximately 50 percent of children at diagnosis and requires targeted therapy. In many cases immune defects affecting cytotoxicity of T cells and natural killer cells underlie the susceptibility to HLH. Autosomal recessive disorders include perforin deficiency (the major cytotoxin of the immune system), or defects in proteins involved in degranulation and exocytosis of perforin and granzyme B (MUNC 13–4, MUNC18-2, STX11, Rab27a). The latter proteins are involved in degranulation generally within the hematopoietic system, thus impacting the function of neutrophils and platelets as well. A rare defect of granulogenesis, Chediak Higashi syndrome, is also associated with a high incidence of HLH. Two forms of X-linked lymphoproliferative syndrome (XLP1 – SAP deficiency, and XLP2 – XIAP deficiency), as well as the rare autosomal recessive disorder ITK (IL-2 inducible T cell kinase) deficiency, are characterized by a high incidence of Epstein-Barr virus-driven HLH and lymphoproliferation. A common pathogenic mechanism underlying these consequences has not yet been elucidated. Effective initial treatment for HLH consists of cytotoxic and anti-inflammatory agents. The most widely used over the past 20 years has been a combination of CNS-penetrating steroid (Decadron) and etoposide. Another approach has been to use anti-thymocyte globulin (ATG) as induction therapy. Both treatments have resulted in approximately 60 percent responses during the first month of therapy. Supportive care with broad-spectrum antimicrobials is a critical adjunct. More recently, a new induction protocol—hybrid immunotherapy for HLH, combining the features of early ATG followed by etoposide, with steroids—has been opened in the United States (http://clinicaltrials.gov/ct2/show/NCT01104025) and Europe. However, HLH persists or reactivates in nearly half of patients as immune suppression is reduced. While a common approach to reactivation is to reintensify previous therapy, no clear guidelines have been developed for this complication. The use of Campath, a humanized monoclonal anti-CD52 antibody, as salvage therapy prior to hematopoietic cell transplantation (HCT) is being tested, as both activated T cells and activated monocyte/macrophages (histiocytes) are targeted through CD52. Historically, the three-year survival after HCT in patients treated with HLH-94 was 60 percent. More recently, use of Campath-based reduced intensity conditioning protocols have led to improved results after HCT. Campath has the advantage of reducing graft-versus-host disease if properly timed prior to HCT. In a recent contemporaneous series of HCT from unrelated adult donors, three-year posttransplant survival improved from 43 percent to 92 percent with no early transplant-related mortality. Disclosures: No relevant conflicts of interest to declare.

scholarly journals COVID-19, T Cells, Cytokines and Immunotherapy: Review

2021 ◽  
pp. 70-82
Author(s):  
Nesrin I. Tarbiah
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Infections ◽  
Cytotoxic T Cells ◽  
Clinical Findings ◽  
Global Pandemic ◽  
Significant Step ◽  
Novel Coronavirus ◽  
Cellular Immune ◽  
Cell Expression

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus (COVID-19), materialized in the city of Wuhan and quickly spread to form a global pandemic. An essential role in the immune system is undertaken by lymphocytes, which defend against bacteria, viruses, fungi, and parasites. Previous study found that very severe COVID-19 patients had suppression of the immune response enabling the virus to spread and cause more damage. This was evident by the changes in their white blood cell and lymphocyte count. Early clinical findings suggest that those suffering from severe COVID-19 have reduced numbers of lymphocytes, monocytes, and other granulocytes. One of the most efficient responses for a variety of viral infections is cellular immune response activation, especially via T cells. Viruses can be eliminated by T cytotoxic (CD8+) (Tc) in the host body, these secrete a variety of molecules, including interferons (IFNs), granzyme, and perforin. T helper (CD4+) (Th) cells help by assisting cytotoxic T cells and B cells to eliminate viral infection. CD8+ and CD4+ work together in a coordinated immune response with other constituents to primarily resolve acute viral infections, and after to produce protection against any reinfection. Also, COVID-19 causes dramatic changes in cytokine profiles and serological markers. Therefore, the subsets of immune cells and the level of the pro-inflammatory cytokines are crucial evidence to determine the severity of COVID-19. The disease severity has already been proved to be associated with the disruption in the proinflammatory chemokine response, this eventually leads to a cytokine storm and progression of cytokines release syndrome (CRS). This review aimed to demonstrate a full understanding of the alterations to the immune response by determining the T-cell expression and cytokine levels against the pathological processes of COVID-19, which can be a significant step in early treatment and diagnosis of this disease, in reduction of COVID-19 mortality cases, and to emphasize the most recent and current studies to try to identify new immuno-therapeutics for COVID-19.  

scholarly journals IMPORTANCE OF HYPERBILURUBINEMIA IN DIFFERENTIATION OF PRIMARY AND SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN PEDIATRIC CASES

2014 ◽  
Vol 6 (1) ◽  
pp. e2014067 ◽  
Author(s):  
Seval Ozen ◽  
Alper Dai ◽  
Enes Coskun ◽  
Serdar Oztuzcu ◽  
Sercan Ergun ◽  
...  
Keyword(s):  
Inflammatory Disease ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Clinical Findings ◽  
Initial Diagnosis ◽  
Direct Bilirubin ◽  
Pediatric Hematology ◽  
Life Threatening ◽  
Secondary Hemophagocytic Lymphohistiocytosis

Background and objective: Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hyper inflammatory disease. It is difficult to differentiate between primary and secondary HLH based on clinical findings at the onset of disease. We aimed to find parameters that can help to differentiate primary and secondary HLH at initial diagnosis especially for physicians working in developing countries.Patient and Method: We retrospectively analyzed data of 38 HLH patients who were admitted to the Pediatric Hematology Department of Gaziantep University between January 2009 and December 2013.Results: Of 38 patients, 20 were defined as primary and 18 were secondary HLH. The average age of primary and secondary HLH patients was 31±9 and 81±14 months, respectively (p=0.03). We found consanguinity rates significantly higher in primary HLH patients compared to secondary HLH patients (p=0.03). We found that total and direct bilirubin levels significantly increased in primary HLH patients compared to secondary HLH patients (p=0.006, p=0.044). Also, CRP levels were found markedly increased in secondary HLH patients compared to primary ones (p=0.017).Conclusion: We showed that cholestasis and hyperbilurubinemia findings of HLH patients at the initial diagnosis should be considered in favor of primary HLH and increased level of CRP should be considered in favor of secondary HLH.

scholarly journals Risk factors for secondary hemophagocytic lymphohistiocytosis in severe coronavirus disease 2019 adult patients

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mei Meng ◽  
Limin Chen ◽  
Sheng Zhang ◽  
Xuan Dong ◽  
Wenzhe Li ◽  
...  
Keyword(s):  
Risk Factors ◽  
Organ Failure ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Viral Infections ◽  
Adult Patients ◽  
Reactive Protein ◽  
Failure Assessment ◽  
Life Threatening ◽  
Independent Risk Factors ◽  
Secondary Hemophagocytic Lymphohistiocytosis

Abstract Background Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event and a fatal complication of viral infections. Whether sHLH may also be observed in patients with a cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still uncertain. We aimed to determine the incidence of sHLH in severe COVID-19 patients and evaluate the underlying risk factors. Method Four hundred fifteen severe COVID-19 adult patients were retrospectively assessed for hemophagocytosis score (HScore). A subset of 7 patients were unable to be conclusively scored due to insufficient patient data. Results In 408 patients, 41 (10.04%) had an HScore ≥169 and were characterized as “suspected sHLH positive”. Compared with patients below a HScore threshold of 98, the suspected sHLH positive group had higher D-dimer, total bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, triglycerides, ferritin, interleukin-6, C-reactive protein, procalcitonin, lactate dehydrogenase, creatine kinase isoenzyme, troponin, Sequential Organ Failure Assessment (SOFA) score, while leukocyte, hemoglobin, platelets, lymphocyte, fibrinogen, pre-albumin, albumin levels were significantly lower (all P < 0.05). Multivariable logistic regression revealed that high ferritin (>1922.58 ng/mL), low platelets (<101 × 109/L) and high triglycerides (>2.28 mmol/L) were independent risk factors for suspected sHLH in COVID-19 patients. Importantly, COVID-19 patients that were suspected sHLH positive had significantly more multi-organ failure. Additionally, a high HScore (>98) was an independent predictor for mortality in COVID-19. Conclusions HScore should be measured as a prognostic biomarker in COVID-19 patients. In particular, it is important that HScore is assessed in patients with high ferritin, triglycerides and low platelets to improve the detection of suspected sHLH.

scholarly journals High expression of CD38 and MHC class II on CD8+ T cells during severe influenza disease reflects bystander activation and trogocytosis

2021 ◽  
Author(s):  
Xiaoxiao Jia ◽  
Brendon Y Chua ◽  
Liyen Loh ◽  
Marios Koutsakos ◽  
Lukasz Kedzierski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Severe Disease ◽  
Mhc Ii ◽  
Cell Responses ◽  
Disease Outcomes ◽  
Hla Dr ◽  
Antigen Presenting ◽  
I Cells

AbstractAlthough co-expression of CD38 and HLA-DR on CD8+ T cells reflects activation during influenza, SARS-CoV-2, Dengue, Ebola and HIV-1 viral infections, high and prolonged CD38+HLA-DR+ expression can be associated with severe and fatal disease outcomes. As the expression of CD38+HLA-DR+ is poorly understood, we used mouse models of influenza A/H7N9, A/H3N2 and A/H1N1 infection to investigate the mechanisms underpinning CD38+MHC-II+ phenotype on CD8+ T-cells. Our analysis of influenza-specific immunodominant DbNP366+CD8+ T-cell responses showed that CD38+MHC-II+ co-expression was detected on both virus-specific and bystander CD8+ T-cells, with increased numbers of both CD38+MHC-II+CD8+ T-cell populations observed in the respiratory tract during severe infection. To understand the mechanisms underlying CD38 and MHC-II expression, we also used adoptively-transferred transgenic OT-I CD8+ T-cells recognising the ovalbumin-derived KbSIINFEKL epitope and A/H1N1-SIINKEKL infection. Strikingly, we found that OT-I cells adoptively-transferred into MHC-II−/− mice did not display MHC-II after influenza virus infection, suggesting that MHC-II was acquired via trogocytosis in wild-type mice. Additionally, detection of CD19 on CD38+MHC II+ OT-I cells further supports that MHC-II was acquired by trogocytosis, at least partially, sourced from B-cells. Our results also revealed that co-expression of CD38+MHC II+ on CD8+ T-cells was needed for the optimal recall ability following secondary viral challenge. Overall, our study provides evidence that both virus-specific and bystander CD38+MHC-II+ CD8+ T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38+MHC II+ phenotype for CD8+ T-cell memory establishment and recall.SummaryCo-expression of CD38 and MHC-II on CD8+ T cells is recognized as a classical hallmark of activation during viral infections. High and prolonged CD38+HLA-DR+ expression, however, can be associated with severe disease outcomes and the mechanisms are unclear. Using our established influenza wild-type and transgenic mouse models, we determined how disease severity affected the activation of influenza-specific CD38+MHC-II+CD8+ T cell responses in vivo and the antigenic determinants that drive their activation and expansion. Overall, our study provides evidence that both virus-specific and bystander CD38+MHC-II+ CD8+ T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs, at least in part, via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38+MHC II+ phenotype for CD8+ T-cell memory establishment and recall.

scholarly journals Generation of glucocorticoid resistant SARS-CoV-2 T-cells for adoptive cell therapy

2020 ◽  
Author(s):  
Rafet Basar ◽  
Nadima Uprety ◽  
Emily Ensley ◽  
May Daher ◽  
Kimberly Klein ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Peripheral Blood ◽  
Gene Editing ◽  
Viral Infections ◽  
Receptor Gene ◽  
Adoptive Cell Therapy ◽  
Culture Conditions ◽  
Glucocorticoid Receptor Gene ◽  
Life Threatening

SUMMARYAdoptive cell therapy with viral-specific T cells has been successfully used to treat life-threatening viral infections, supporting the application of this approach against COVID-19. We expanded SARS-CoV-2 T-cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observed that the choice of cytokines modulates the expansion, phenotype and hierarchy of antigenic recognition by SARS-CoV-2 T-cells. Culture with IL-2/4/7 but not other cytokine-driven conditions resulted in >1000 fold expansion in SARS-CoV-2 T-cells with a retained phenotype, function and hierarchy of antigenic recognition when compared to baseline (pre-expansion) samples. Expanded CTLs were directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T-cells could not be efficiently expanded from the peripheral blood of non-exposed controls. Since corticosteroids are used for the management of severe COVID-19, we developed an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.

Pneumonitis in patients with thymoma and Good's syndrome.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20595-e20595
Author(s):  
Margaret Ottaviano ◽  
Pietro De Placido ◽  
Erica Pietroluongo ◽  
Marianna Tortora ◽  
Fernanda Picozzi ◽  
...  
Keyword(s):  
T Cells ◽  
Intensive Care ◽  
B Cells ◽  
Viral Infections ◽  
Disease Stage ◽  
Blood Levels ◽  
Histopathological Diagnosis ◽  
Good’S Syndrome ◽  
Rare Tumours ◽  
Life Threatening

e20595 Background: The association between thymoma (T) and immunological dysregulations is well acknowledged. Good’s syndrome (GS), which occurs in approximately 6% to 11% of T patients, is characterized by hypogammaglobulinemia, few or absent B-cells (CD19+), CD4 T cells lymphopenia, abnormal CD4/CD8 T ratio and impaired T cell mitogenic response. Patients with GS have increased susceptibility to bacterial, opportunistic and viral infections related to both humoral and cell-mediated immunodeficiency. The recent Sars-Cov-2 pandemic drew attention to the clinical condition of fatal viral pneumonitis and cytokines storm. Here we reported our monocentric experience of pneumonitis in patients with T and GS before the Sars-Cov-2 pandemic. Methods: We conducted a retrospective analysis of T patients with associated GS referred to the Rare Tumours Reference Center of University Federico II of Naples over a 10-year period (from 2009 to 2019). All the patients with radiological and/or clinical pneumonitis diagnosis were evaluated for this report. Immunological features, histopathological diagnosis and clinical outcome were registered. Results: A total of 41 patients with T and GS were identified, including 17 patients with local disease (stage I-II according to Masaoka-Koga) and 24 with advanced disease (stage III-IV). The majority (56.3%) had B2 T diagnosis. Radiological and/or clinical pneumonitis diagnosis was assessed in 23 cases (56%). Viral pneumonitis was detected in 8 patients: 3 patients with H1N1 infection, 3 patients with CMV infection, 2 patients with EBV infection. Bacterial pneumonitis was diagnosed in 9 patients (3 patients with K. pneumoniae, 4 patients with S. aureus, 2 patients with H. influenza). Opportunistic pneumonitis was found in 2 patients with Aspergillosis infection. In 2 cases no pathogenic agent was identified. The immunophenotyping, assessed in 4 patients with viral pneumonitis, displayed very low/undetectable levels of B cells, with median % value of CD3+T cells and NKT of respectively 9.8% and 0.4% of the total leukocytes. The median % of Treg was 4.7%. CD4+/CD8+ ratio was variable, ranging from 1,2 to 0,6. Interestingly the number of B cells was extremely low, independent of CD4+/CD8+ ratio. Blood levels of cytokines, chemokines and growth factors revealed elevated IL-4, Eotaxin, CCL2 / MCP-1 and CCL5 / RANTES ad strong reduction of IL-10. PDGF-BB levels were also elevated. 15 patients required admission to intensive care Six patients died for fatal pneumonitis. Conclusions: The management of T patients with GS is extremely challenging. Clear diagnostic algorithms do not yet exist and immune-profiling and quantitative immunoglobulins should be considered a part of diagnostic search in these patients. The coexistence of cancer, infections and immunosuppression may trigger life-threatening conditions, such as fatal pneumonitis, which often require intensive care and multidisciplinary approach.

Excessive Anti-Viral CD8 T Cell Activation Inverts the IL-2 Consumptive Hierarchy Triggering Regulatory T Cell Collapse in Mouse Model for Hemophagocytic Lymphohistiocytosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1025-1025
Author(s):  
Stephanie Humblet-Baron ◽  
Dean Franckaert ◽  
Simon Bornschein ◽  
Bénédicte Cauwe ◽  
Susann Schonefeldt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Life Threatening ◽  
Deficient Mice

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8+ T cell activation. HLH occurs in both acquired and familial (FHL) forms, with mutations in Perforin being a common cause of FHL. In both conditions a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent advances using experimental FHL triggered by lymphocytic choriomeningitis virus (LCMV) in Perforin-deficient mice have attributed the key distal event to be excessive IFNγ production, however the proximal events driving immune dysregulation have remained undefined. We investigated the role of regulatory T cells (Tregs) in the pathophysiology of experimental FHL. While we found no primary Treg defects in Perforin-deficient mice, Treg numbers collapsed following LCMV inoculation. The collapse of Treg numbers in LCMV-triggered Perforin-deficient, but not wildtype, mice was driven by the combination of lower IL-2 secretion by conventional CD4+ T cells, increased IL-2 consumption by activated CD8+ T cells and secretion of competitive sCD25 (IL-2 receptor). Together, these data demonstrate that excessive CD8+ T cell activation rewires the IL-2 homeostatic network away from Treg maintenance and towards feed-forward inflammation. In addition, reduced Treg number may contribute to the massive inflammation found in FHL. Disclosures No relevant conflicts of interest to declare.

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