scholarly journals Massive clonal expansion of polycytotoxic skin and blood CD8+ T cells in patients with toxic epidermal necrolysis

2021 ◽  
Vol 7 (12) ◽  
pp. eabe0013
Author(s):  
Axel Patrice Villani ◽  
Aurore Rozieres ◽  
Benoît Bensaid ◽  
Klara Kristin Eriksson ◽  
Amandine Mosnier ◽  
...  
Keyword(s):  
T Cells ◽  
Toxic Epidermal Necrolysis ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Effector Memory ◽  
Skin Symptoms ◽  
Tcr Repertoire ◽  
Repertoire Sequencing ◽  
Life Threatening ◽  
Cutaneous Adverse Drug Reaction

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8+ T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient’s blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions.

Cytotoxic minor histocompatibility antigen HA-1–specific CD8+ effector memory T cells: artificial APCs pave the way for clinical application by potent primary in vitro induction

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 144-149 ◽  
Author(s):  
Karin Schilbach ◽  
Gunter Kerst ◽  
Steffen Walter ◽  
Matthias Eyrich ◽  
Dorothee Wernet ◽  
...  
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Histocompatibility Antigen ◽  
Effector Memory ◽  
Minor Histocompatibility Antigen ◽  
Tcr Repertoire ◽  
Long Time ◽  
In Vitro Induction

Induction of cytotoxic T lymphocytes (CTLs) for treatment of relapsed leukemia after allogeneic stem-cell transplantation is hindered by the laborious and time-consuming procedure of generating dendritic cells for antigen presentation. Artificial antigen-presenting cells (aAPCs) offer the advantage of being readily available in sufficient numbers, thus allowing for a highly standardized in vitro induction of CTLs. We generated aAPCs coated with anti-CD28 antibody (Ab) and either high-density (HD) or low-density (LD) major histocompatibility complex (MHC) class I molecules loaded with HA-1H, a nonapeptide derived from the hematopoiesis-restricted minor histocompatibility antigen HA-1. HD- and LD-aAPCs potently induced HA-1H–specific CD8+ CTLs from untouched CD8+ T cells of healthy donors. CTLs were subsequently purified by magnetic-activated cell sorting. HD- as well as LD-aAPC–induced CTLs exerted high HA-1H–specific cytotoxicity, resembled Tc1 effector memory cells, survived a long time in vitro, and were expanded by a factor varying between 8.2 × 104 and 51 × 104. The T-cell receptor (TCR) repertoire of HA-1H tetramer–positive CTLs was oligoclonal with a prominent usage of Vβ6. The TCR repertoire of tetramer-positive CTLs was distinct from and more restricted than that of tetramer-negative cells. These findings indicate that aAPCs are attractive tools for the ex vivo generation of HA-1H–specific CTLs suitable for immunotherapy of relapsed leukemia.

scholarly journals MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Lauren J. Howson ◽  
Giorgio Napolitani ◽  
Dawn Shepherd ◽  
Hemza Ghadbane ◽  
Prathiba Kurupati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Receptor ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Mait Cells ◽  
Vaccination Strategies ◽  
Human Volunteers ◽  
Tcr Repertoire ◽  
Cell Clonal Expansion ◽  
Mait Cell

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.

scholarly journals Profiling virus-specific Tcf1+ T cell repertoires during acute and chronic viral infection

2020 ◽  
Author(s):  
Alexander Yermanos ◽  
Ioana Sandu ◽  
Alessandro Pedrioli ◽  
Mariana Borsa ◽  
Franziska Wagen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Clonal Diversity ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Tcr Repertoire ◽  
Repertoire Sequencing ◽  
Lcmv Infection

AbstractCD8 T cells play a crucial role in providing protection from viral infections. It has recently been established that a subset of CD8 T cells expressing Tcf1 are responsible for sustaining exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection. Many of these studies, however, have been performed using T cell receptor (TCR) transgenic mice, in which CD8 T cells express a monoclonal TCR specific for the LCMV glycoprotein. To investigate whether the Tcf1+ and Tcf1-repertoires are naturally composed of similar or different clones in wild-type mice exposed to acute or chronic LCMV infection, we performed TCR repertoire sequencing of virus-specific CD8 T cells, including Tcf1+ and Tcf1-populations. Our analysis revealed that the Tcf1+ TCR repertoire is maintained at an equal or higher degree of clonal diversity despite harboring fewer cells. Additionally, within the same animal, there was extensive clonal overlap between the Tcf1+ and Tcf1-repertoires in both chronic and acute LCMV infection. We could further detect these virus-specific clones in longitudinal blood samples earlier in the infection. With respect to common repertoire parameters (clonal overlap, germline gene usage, and clonal expansion), we found minor differences between the virus-specific TCR repertoire of acute and chronic LCMV infection 40 days post infection. Overall, our results indicate that the Tcf1+ population emerging during chronic LCMV infection is not clonally distinct from the Tcf1-population, supporting the notion that the Tcf1+ pool is indeed a fuel for the more exhausted Tcf1-population within the heterogenous repertoire of LCMV-specific CD8 T cells.

Lenalidomide (CC5013, Revlimid®) Alters a T Cell Homeostatic Check-Point in Patients with Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 851-851
Author(s):  
JianXiang Zou ◽  
Edna Ku ◽  
Fanqi Bai ◽  
Jeffrey S. Painter ◽  
Alan F. List ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Effector Memory ◽  
T Cell Proliferation ◽  
Memory Cells ◽  
Tcr Repertoire ◽  
Effector Memory Cells

Abstract Background: Myelodysplastic Syndromes (MDS) are a diverse group of myeloid malignancies that occur primarily in older individuals. Several distinct immunologic abnormalities have been described in MDS, including concurrent autoimmune diseases, inversion of CD4+ and CD8+ cell populations, and expansion hematopoietic inhibitory) CD8+ T cell clones. Suppression of hematopoiesis by T cells has been implicated in the pathogenesis of ineffective hematopoiesis in a select subpopulation of patients with response to immunosuppressive therapy. Immunologic abnormalities in MDS patients may relate to the process of immunologic aging associated with functional deterioration. Lenalidomide (CC5013, Revlimid®, Celgene Inc) is a member of a proprietary drug class known as immunomodulatory drugs (IMiDs) with strong and sustained hematological activity in MDS patients. The goal of this study was to investigate the in vitro and in vivo actions of lenalidomide on T cell immune functions and homeostasis in MDS patients. Methods: Using peripheral blood mononuclear cells (PBMCs), we analyzed T cell subpopulations and function in 11 MDS patients and 12 controls of similar age. Naïve and memory CD4 and CD8 T cell sub-populations were segregated by expression of CD45RA and CD62L expression by flow cytometry. After antigen activation with anti-CD3-cross-linking and allogeneic dendritic cells (allo-DCs), T cell proliferation was assessed by Brdu incorporation in CD4+ and CD8+ T cells, and intracellular cytokines determined by flow cytometry. T cell receptor (TCR) repertoire skewing was determined by CDR3-length analysis on 53 patients. In vivo action of lenalidomide was evaluated in PBMCs from seven patients (4 erythroid complete responders and 3 non-responders) taken pre- and post-treatment. Results: Patients with MDS had reduced T cell proliferation and impaired Th1 cytokine response after antigen stimulation compared to age-matched controls. No correlation was found between patient age and percentage of proliferating antigen-induced CD4− or CD8− T cells (r=0.13, p=0.6 and r=−0.17, p=0.5, respectively). Phenotype analysis showed that the percentage of CD4+ and CD8+/CD45RA+/CD62L+−naïve T cells were significantly reduced, whereas, CD4+ and CD8+/CD45RA−/CD62L−double-negative effector memory cells were significantly increased in MDS patients. Furthermore, 50% of MDS patients displayed a skewed T cell receptor repertoire that was not age-dependent. Of the MDS patients treated with lenalidomide, the four responders displayed a significant increase in antigen-induced T cell proliferation and increased Th1-type cytokine secretion, whereas no changes were observed in non-responders. Moreover, CD4+ (P=0.001) and CD8+ (P=0.06) T cells with a naïve phenotype increased accompanied by augmentation in the percentage of CD8+ central memory T cells (P=0.02); whereas, the percentage of CD4+ effector memory cells decreased (p=0.001) in lenalidomide responders but not in non-responders. Conclusions: These data suggest that MDS patients possess multiple T cell defects including age-independent TCR repertoire skewing, reduction in naïve T cells, and accumulation of effector memory cells that are improved by lenalidomide. Our findings suggest hematopoietic response to lenalidomide may relate to a novel capacity to restore T cell homeostasis.

scholarly journals Genetic analysis of low V beta 3 expression in humans.

1994 ◽  
Vol 179 (5) ◽  
pp. 1701-1706 ◽  
Author(s):  
J P Donahue ◽  
N S Ricalton ◽  
C E Behrendt ◽  
C Rittershaus ◽  
S Calaman ◽  
...  
Keyword(s):  
T Cells ◽  
Large Family ◽  
Cell Receptor ◽  
Recessive Trait ◽  
Similar Frequency ◽  
Normal Individuals ◽  
Tcr Repertoire ◽  
Fetal Cord Blood ◽  
Low Levels ◽  
Low Expression

While studying the T cell receptor (TCR) repertoire of normal individuals, we found that more than 20% of adults have low levels of circulating V beta 3.1+ T cells in both CD4 and CD8 populations. A similar frequency was found in fetal cord blood samples, suggesting that in most cases, the V beta 3.1low phenotype is inherited. In support of this conclusion, children expressing low levels were only found in families where one of the parents expressed this phenotype. In two large families, genetic studies showed that low expression was a recessive trait and dependent on inheritance of particular TCR VB gene complexes. Family members with the low phenotype, however, expressed VB3.1 genes with normal sequences and expressed normal levels of receptor per cell. Results from these families suggest that up to 50% of normal individuals may carry a VB3.1 allele that is defective in its ability to rearrange effectively. In another large family, low expression in one individual was shown not to be determined by genes within the TCR VB gene or major histocompatibility complexes, suggesting a different mechanism for low V beta 3.1+ T cells. Overall, our results describe novel mechanisms that result in low levels of V beta 3.1+ T cells in a relatively large subset of the normal human population.

scholarly journals CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

2004 ◽  
Vol 200 (11) ◽  
pp. 1407-1417 ◽  
Author(s):  
Adrian F. Ochsenbein ◽  
Stanley R. Riddell ◽  
Michele Brown ◽  
Lawrence Corey ◽  
Gabriela M. Baerlocher ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Receptor ◽  
Effector Memory ◽  
Term Survival ◽  
Functional Consequences

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response.

The T-cell receptor Vβgene repertoire and clonal expansion from peripheral blood T cells in benzene-exposed workers in China

Hematology ◽  
2009 ◽  
Vol 14 (2) ◽  
pp. 106-110 ◽  
Author(s):  
Bo Li ◽  
Yangqiu Li ◽  
Shaohua Chen ◽  
Lijian Yang ◽  
Wei Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Exposed Workers

scholarly journals Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

2017 ◽  
Vol 214 (11) ◽  
pp. 3417-3433 ◽  
Author(s):  
Xiaojing Chen ◽  
Lucia Poncette ◽  
Thomas Blankenstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Mhc Molecules ◽  
Mhc Ii ◽  
Cdr3 Length ◽  
Tcr Repertoire ◽  
Cell Diversity ◽  
Antigen Presenting

For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.

scholarly journals Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI

2021 ◽  
Author(s):  
Christian R Schultze-Florey ◽  
Leonie Kuhlmann ◽  
Solaiman Raha ◽  
Joana Barros-Martins ◽  
Ivan Odak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Prospective Clinical Study ◽  
Hematopoietic Stem ◽  
Graft Versus Leukemia ◽  
Αβ T Cells ◽  
Durable Remission

Donor lymphocyte infusion (DLI) is a standard of care for relapse of AML after allogeneic hematopoietic stem cell transplantation (aHSCT). Currently it is poorly understood how and when CD8+ αβ T cells exert graft-versus-leukemia (GvL) activity after DLI. Also, there is no reliable biomarker to monitor GvL activity of the infused CD8+ T cells. Therefore, we analyzed the dynamics of CD8+ αβ T cell clones in DLI-patients. In this prospective clinical study of 29 patients, we performed deep T cell receptor β (TRB) sequencing of sorted CD8+ αβ T cells to track patients' repertoire changes in response to DLI. Upon first occurrence of GvL, longitudinal analyses revealed a preferential expansion of distinct CD8+ TRB clones (n=14). This did not occur in samples of patients without signs of GvL (n=11). Importantly, early repertoire changes 15 days after DLI predicted durable remission for the 36 months study follow-up. Furthermore, absence of clonal outgrowth of the CD8+ TRB repertoire after DLI was an early biomarker that predicted relapse at a median time of 11.2 months ahead of actual diagnosis. Additionally, unbiased sample analysis regardless of the clinical outcome revealed that patients with decreasing CD8+ TRB diversity at day 15 after DLI (n=13) had a lower relapse incidence (P=0.0040) compared to patients without clonal expansion (n=6). In conclusion, CD8+ TRB analysis may provide a reliable tool for predicting the efficacy of DLI and holds the potential to identify patients at risk for progression and relapse after DLI.

scholarly journals In vitro maintaining of CD4+ central and effector memory cells in normal and inflammatory conditions

2020 ◽  
Vol 22 (5) ◽  
pp. 837-846
Author(s):  
E. A. Blinova ◽  
A. V. Kolerova ◽  
V. E. Balyasnikov ◽  
V. A. Kozlov
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Cell Receptor ◽  
Whole Body ◽  
Effector Memory ◽  
Adherent Cell ◽  
Memory Cells ◽  
Inflammatory Conditions ◽  
Low Sensitivity

IL-7 is a key factor for the survival and maintenance of CD4+ central (Tcm) and effector (Tem) memory cells in the whole body. In many autoimmune diseases, an elevated level of IL-7 is detected in blood serum and at the site of inflammation, thus suggesting participation of this homeostatic factor in the survival of memory T cells, including auto-reactive clones, in inflammatory disorders. The aim of the study was to investigate the mechanisms of maintaining CD4+ memory T cells under normal and inflammatory conditions. We developed an in vitro model of inflammation, based on induction of pro-inflammatory cytokines, and then evaluated the effects of IL-7 upon purified sorted populations of CD4+Tcm and Tem under normal conditions and in vitro inflammatory model. IL-7 treatment promoted maintenance of CD4+Tcm phenotype in all variants of cultures. In the absence of contact with adherent cell fraction, the IL-7-induced proliferation of Tcm and Tem was slightly reduced, both under normal and inflammatory conditions, thus suggesting low sensitivity of memory T cells to contacts with MHC, and, probably, a requirement for additional signals to provide complete stimulation with IL-7. The last suggestion is also supported by data about CD127 and CD132 expression, i.e., in the absence of contact with MHC, the proportion of CD127+CD132+ cells was decreased in both subpopulations of CD4+ memory cells. Upon in vitro cultures, IL-7 contributed to decreased expression of CD127, and increased expression of CD132 on CD4+Tcm and Tem. We have evaluated the CD4+Tcm and Tem populations by affinity of T cell receptor (TCR), using the level of CD5 expression. Т cells with high TCR affinity for self-antigens are known to have higher expression of CD5. In comparison to Tem, the Tcm contained more CD5high cells. In cultures, IL-7 promoted a high level of CD5 expression on Tcm, which was comparable to levels observed in peripheral blood cells. High CD5 expression on Tem was observed after stimulation with IL-7 in the in vitro inflammatory model. In the absence of contact with MHC, the number of CD5high cells decreased among CD4+Tem and Tcm. Thus, CD4+Tcm cells with high affinity for autologous antigens are probably dependent on the presence of homeostatic factors, in particular, IL-7, and contacts with antigen-presenting cells (APCs). Under conditions of inflammation, no changes were revealed in the mechanism of maintaining CD4+Tcm, in contrast to CD4+Tem. Being less dependent on IL-7 under normal conditions, CD4+CD5highTem are accumulated in the presence of IL-7 under in vitro inflammatory conditions.

Sign in / Sign up

Export Citation Format

Share Document