scholarly journals PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001631
Author(s):  
Sylvain Simon ◽  
Valentin Voillet ◽  
Virginie Vignard ◽  
Zhong Wu ◽  
Camille Dabrowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Therapeutic Response ◽  
Immune Cell ◽  
Expression Profiles ◽  
Cell Subset ◽  
Phenotypic Characterization ◽  
Multiparameter Flow Cytometry ◽  
Specific Gene

BackgroundClinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.MethodsWe isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets.ResultsWe documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1 month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response.ConclusionsOur results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.

scholarly journals The Activated Type 1–Polarized Cd8+ T Cell Population Isolated from an Effector Site Contains Cells with Flexible Cytokine Profiles

1999 ◽  
Vol 190 (8) ◽  
pp. 1081-1092 ◽  
Author(s):  
Anthony G. Doyle ◽  
Kathy Buttigieg ◽  
Penny Groves ◽  
Barbara J. Johnson ◽  
Anne Kelso
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Expression Profiles ◽  
Lung Parenchyma ◽  
Activated T Cells ◽  
Cytokine Genes ◽  
Effector Site

The capacity of activated T cells to alter their cytokine expression profiles after migration into an effector site has not previously been defined. We addressed this issue by paired daughter analysis of a type 1–polarized CD8+ effector T cell population freshly isolated from lung parenchyma of influenza virus–infected mice. Single T cells were activated to divide in vitro; individual daughter cells were then micromanipulated into secondary cultures with and without added IL-4 to assess their potential to express type 2 cytokine genes. The resultant subclones were analyzed for type 1 and 2 cytokine mRNAs at day 6–7. When the most activated (CD44highCD11ahigh) CD8+ subpopulation from infected lung was compared with naive or resting (CD44lowCD11alow) CD8+ cells from infected lung and from normal lymph nodes (LNs), both clonogenicity and plasticity of the cytokine response were highest in the LN population and lowest in the activated lung population, correlating inversely with effector function. Multipotential cells were nevertheless detected among clonogenic CD44highCD11ahigh lung cells at 30–50% of the frequency in normal LNs. The data indicate that activated CD8+ T cells can retain the ability to proliferate and express new cytokine genes in response to local stimuli after recruitment to an effector site.

Association between cetuximab response and differential immunologic gene expression signatures in colorectal cancer metastases.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 558-558 ◽  
Author(s):  
Michael Sangmin Lee ◽  
Benjamin Garrett Vincent ◽  
Autumn Jackson McRee ◽  
Hanna Kelly Sanoff
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Activated T Cells ◽  
Gene Sets

558 Background: Different immune cell infiltrates into colorectal cancer (CRC) tumors are associated with different prognoses. Tumor-associated macrophages contribute to immune evasion and accelerated tumor progression. Conversely, tumor infiltrating lymphocytes at the invasive margin of CRC liver metastases are associated with improved outcomes with chemotherapy. Cetuximab is an IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) and stimulates antibody-dependent cellular cytotoxicity (ADCC) in vitro. However, it is unclear in humans if response to cetuximab is modulated by the immune response. We hypothesized that different immune patterns detected in gene expression profiles of CRC metastases are associated with different responses to cetuximab. Methods: We retrieved gene expression data from biopsies of metastases from 80 refractory CRC patients treated with cetuximab monotherapy (GEO GSE5851). Samples were dichotomized by cetuximab response as having either disease control (DC) or progressive disease (PD). We performed gene set enrichment analysis (GSEA) with GenePattern 3.9.4 using gene sets of immunologic signatures obtained from the Molecular Signatures Database v5.0. Results: Among the 68 patients with response annotated, 25 had DC and 43 had PD. In the PD cohort, 59/1910 immunologic gene sets had false discovery rate (FDR) < 0.1. Notably, multiple gene sets upregulated in monocyte signatures were associated with PD. Also, gene sets consistent with PD1-ligated T cells compared to control activated T cells (FDR = 0.052) or IL4-treated CD4 T cells compared to controls (FDR = 0.087) were associated with PD. Conclusions: Cetuximab-resistant patients tended to have baseline increased expression of gene signatures reflective of monocytic infiltrates, consistent with also having increased expression of the IL4-treated T-cell signature. Cetuximab resistance was also associated with increased expression of the PD1-ligated T cell signature. These preliminary findings support further evaluation of the effect of differential immune infiltrates in prognosis of metastatic CRC treated with cetuximab.

scholarly journals Regulation of Th1 T Cell Differentiation by Iron via Upregulation of T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3)

2021 ◽  
Vol 12 ◽  
Author(s):  
Christa Pfeifhofer-Obermair ◽  
Piotr Tymoszuk ◽  
Manfred Nairz ◽  
Andrea Schroll ◽  
Gloria Klais ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Iron Supplementation ◽  
Immune Cell ◽  
Cell Subset ◽  
Essential Element ◽  
T Cell Differentiation ◽  
Intracellular Pathogens ◽  
Iron Loading

Iron plays an important role in host–pathogen interactions, in being an essential element for both pathogen and host metabolism, but also by impacting immune cell differentiation and anti-microbial effector pathways. Iron has been implicated to affect the differentiation of T lymphocytes during inflammation, however, so far the underlying mechanism remained elusive. In order to study the role of iron in T cell differentiation we here investigated how dietary iron supplementation affects T cell function and outcome in a model of chronic infection with the intracellular bacterium Salmonella enterica serovar typhimurium (S. Typhimurium). Iron loading prior to infection fostered bacterial burden and, unexpectedly, reduced differentiation of CD4+ T helper cells type 1 (Th1) and expression of interferon-gamma (IFNγ), a key cytokine to control infections with intracellular pathogens. This effect could be traced back to iron-mediated induction of the negative immune checkpoint regulator T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), expressed on the surface of this T cell subset. In vitro experiments demonstrated that iron supplementation specifically upregulated mRNA and protein expression of TIM-3 in naïve Th cells in a dose-depdendent manner and hindered priming of those T cells towards Th1 differentiation. Importantly, administration of TIM-3 blocking antibodies to iron-loaded mice infected with S. Typhimurium virtually restored Th1 cell differentiation and significantly improved bacterial control. Our data uncover a novel mechanism by which iron modulates CD4+ cell differentiation and functionality and hence impacts infection control with intracellular pathogens. Specifically, iron inhibits the differentiation of naive CD4+ T cells to protective IFNγ producing Th1 lymphocytes via stimulation of TIM-3 expression. Finally, TIM-3 may serve as a novel drug target for the treatment of chronic infections with intracellular pathogens, specifically in iron loading diseases.

scholarly journals Bone Marrow-Resident Vδ1 T Cells Co-express TIGIT With PD-1, TIM-3 or CD39 in AML and Myeloma

2021 ◽  
Vol 8 ◽  
Author(s):  
Franziska Brauneck ◽  
Pauline Weimer ◽  
Julian Schulze zur Wiesch ◽  
Katja Weisel ◽  
Lisa Leypoldt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Hematologic Malignancies ◽  
Cell Subpopulation ◽  
Multiparameter Flow Cytometry ◽  
Dependent Manner

Background: γδ T cells represent a unique T cell subpopulation due to their ability to recognize cancer cells in a T cell receptor- (TCR) dependent manner, but also in a non-major histocompatibility complex- (MHC) restricted way via natural killer receptors (NKRs). Endowed with these features, they represent attractive effectors for immuno-therapeutic strategies with a better safety profile and a more favorable anti-tumor efficacy in comparison to conventional αβ T cells. Also, remarkable progress has been achieved re-activating exhausted T lymphocytes with inhibitors of co-regulatory receptors e.g., programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and of the adenosine pathway (CD39, CD73). Regarding γδ T cells, little evidence is available. This study aimed to immunophenotypically characterize γδ T cells from patients with diagnosed acute myeloid leukemia (AML) in comparison to patients with multiple myeloma (MM) and healthy donors (HD).Methods: The frequency, differentiation, activation, and exhaustion status of bone marrow- (BM) derived γδ T cells from patients with AML (n = 10) and MM (n = 11) were assessed in comparison to corresponding CD4+ and CD8+ T cells and peripheral blood- (PB) derived γδ T cells from HDs (n = 16) using multiparameter flow cytometry.Results: BM-infiltrating Vδ1 T cells showed an increased terminally differentiated cell population (TEMRAs) in AML and MM in comparison to HDs with an aberrant subpopulation of CD27−CD45RA++ cells. TIGIT, PD-1, TIM-3, and CD39 were more frequently expressed by γδ T cells in comparison to the corresponding CD4+ T cell population, with expression levels that were similar to that on CD8+ effector cells in both hematologic malignancies. In comparison to Vδ2 T cells, the increased frequency of PD-1+-, TIGIT+-, TIM-3+, and CD39+ cells was specifically observed on Vδ1 T cells and related to the TEMRA Vδ1 population with a significant co-expression of PD-1 and TIM-3 together with TIGIT.Conclusion: Our results revealed that BM-resident γδ T cells in AML and MM express TIGIT, PD-1, TIM-3 and CD39. As effector population for autologous and allogeneic strategies, inhibition of co-inhibitory receptors on especially Vδ1 γδ T cells may lead to re-invigoration that could further increase their cytotoxic potential.

scholarly journals Phenotypic Characterization of Circulating CD4+ T Cells in ANCA-Associated Vasculitis

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Sandra Lilliebladh ◽  
Åsa Johansson ◽  
Åsa Pettersson ◽  
Sophie Ohlsson ◽  
Thomas Hellmark
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chemokine Receptors ◽  
Th17 Cells ◽  
Cell Subset ◽  
Effector Memory ◽  
Phenotypic Characterization ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Cytokines And Chemokines

T cell-mediated immune responses are thought to play an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody- (ANCA-) associated vasculitides (AAV). CD4+ T cells can be divided into subsets depending on their expression of chemokine receptors. In this study, different CD4+ T cell populations in patients with AAV were analysed and compared to healthy blood donors as well as therapy controls. 18 patients with active AAV, 46 in remission, 21 healthy controls (HBD), and 15 therapy controls (TC) were enrolled. CD4+ T cells were divided into Th1, Th2, and Th17 cells and further subdivided into naïve, central memory, effector memory, and effector cells. Regulatory T cells were also analysed. Concentrations of cytokines and chemokines produced by the respective CD4+ T cell subset in plasma from 33 of the patients were measured by ELISA and compared to HBD. Clinical data were collected on all patients. CCL20 concentrations and percentages of Th17 cells (p=0.019) were elevated in AAV patients compared to HBD. AAV patients had lower percentages of naïve CD4+ T cells (p=0.0016) and a corresponding increase in proportion of effector memory CD4+ T cells when comparing to HBD (p=0.027). Therapy controls showed similar results as AAV patients. In this study, we found that CD4+ T cell phenotype distribution is altered in AAV patients, in line with previously published work. However, no differences were found between AAV patients and TC, stressing the importance of treatment impact on this kind of studies.

scholarly journals 796 ALG.APV-527: a 5T4 tumor directed bispecific approach utilizing ADAPTIRTM technology designed for conditional 4-1BB T cell/NK agonism against solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A831-A831
Author(s):  
Michelle Nelson ◽  
Anette Sundstedt ◽  
Yago Pico de Coaña ◽  
Ashly Lucas ◽  
Anneli Nilsson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Immune Cell ◽  
Expression Profiles ◽  
Transcriptional Profiling ◽  
Sequencing Data ◽  
Multiple Tumor

Background4-1BB (CD137) is an activation-induced co-stimulatory receptor that regulates immune responses of activated CD8+ T cells and NK cells. Leveraging the therapeutic benefit of 1st generation 4-1BB monospecifics has been challenging due to dose limiting hepatotoxicity. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel 4-1BB x 5T4 bispecific antibody that stimulates 4-1BB function only when co-engaged with 5T4, a highly selective tumor-associated antigen. The combined preclinical dataset presented here provides an overview of the potential indication landscape, mechanism of action and the efficacy and safety profile of ALG.APV-527, supporting its advancement into the clinic.MethodsGenevestigator Software was used to analyze curated transcriptomic data from bulk tumor mRNA-sequencing data libraries and from single cell RNA-seq libraries for the expression profiles of CD8, 4-1BB and 5T4 across selected human solid tumor datasets. ADCC and ADCP reporter bioassays were utilized to assess Fc engagement by ALG.APV-527. For in vitro tumor lysis studies, human T cells were co-cultured with labelled tumor cells and sub-optimally activated with anti-CD3. Cytotoxicity of tumor cells were continually assessed using a Live-Cell Analysis System.ResultsDual expression of CD8 and 5T4 occurred in many tumor types and correlated well with indications that are pursued in the clinical development of ALG.APV-527. 4-1BB expression was observed in tumor-derived lymphoid subpopulations, especially in those with an exhausted phenotype. Since ALG.APV-527 is designed with a non-Fcγ receptor binding Fc, minimal ADCC & ADCP was induced in vitro. Additionally, ALG.APV-527 enhanced primary immune cell-mediated killing of 5T4-expressing tumor cells when compared to anti-CD3 alone, demonstrating the potential benefit of 4-1BB agonism for enhancing cytotoxic anti-tumor responses in the clinic.ConclusionsALG.APV-527 is designed to elicit safe and efficacious 4-1BB-mediated antitumor activity in a range of 5T4-expressing tumor indications. Transcriptional profiling of patient tumor samples demonstrates 4-1BB expression in multiple tumor-infiltrating lymphocyte subsets and identifies potential indications with 5T4 expression and CD8+ T cell infiltration. The unique design of the molecule minimizes systemic immune activation and hepatotoxicity, allowing for highly efficacious tumor-specific responses as demonstrated by potent activity in in vitro models. Based on these preclinical data, ALG.APV-527 is a promising anti-cancer therapeutic for the treatment of a variety of 5T4-expressing solid tumors and is progressing towards a phase I clinical trial in 2021.

scholarly journals T cell abnormalities in NZB mice occur independently of autoantibody production.

1981 ◽  
Vol 153 (2) ◽  
pp. 221-234 ◽  
Author(s):  
J D Taurog ◽  
E S Raveche ◽  
P A Smathers ◽  
L H Glimcher ◽  
D P Huston ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Population ◽  
Cell Subset ◽  
Precursor Cell ◽  
Autoantibody Production ◽  
X Chromosomes ◽  
Common Precursor ◽  
T Cell Regulation

By means of a series of crosses and backcrosses, ZB.CBA/N mice were prepared bearing largely NZB autosomal genes, but having X chromosomes derived only from CBA/N mice. The CBA/N X chromosome carries a gene, xid, that is associated with the lack of a B cell subset necessary for most of the spontaneous autoantibody production by NZB mice. These ZB.CBA/N mice failed to develop autoantibodies to T cells, erythrocytes, or DNA. The availability of mice that were mostly NZB, but which failed to make autoantibodies, especially anti-T cell antibodies, allowed us to study possible T cell regulatory defects in NZB mice in the absence of either antibodies reactive with such T cells or other autoantibodies. We found that such mice had derangements of T cell regulation as did the NZB mice. These observations strongly suggest that the t cell abnormalities of NZB mice are not caused by the B cell hyperactivity of these mice, but rather represent independent defects. Thus, NZB mice appear to have primary defects in both the B cell population and the T cell population. Whether or not these are separate, or derive from a common precursor cell abnormality, remains to be determined.

scholarly journals Research progress on the role of immune cells in Brucella infection

2018 ◽  
Vol 7 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Jin Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Subset ◽  
Animal Husbandry ◽  
Research Progress ◽  
Human Beings ◽  
T Cell Subset ◽  
Th2 Cell

Abstract Brucellosis is one of the most prevalent zoonoses in the world. Incidence of the disease has increased significantly in recent years and has seriously affected the health of human beings and the development of animal husbandry. The pathogenesis of brucellosis remains unclear. Current studies suggest that this disease may be related to changes in natural killer cells, dendritic cells, and macrophages in immune cell subsets. Brucellosis may be also related to T helper (Th) 1 cell/Th2 cell imbalance in the CD4+ T cell subset, immunoregulation of regulatory T cells and Th17 cells, and the mechanism of action of CD8+ T cell. This paper aims to review the research progress on these inherent immune cells, the CD4+ T cell subset, and CD8+ T cells in Brucella infection.

scholarly journals Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component

2021 ◽  
Vol 12 ◽  
Author(s):  
Lauren Daniel ◽  
Marion Tassery ◽  
Clara Lateur ◽  
Antoine Thierry ◽  
André Herbelin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Cmv Infection ◽  
Senescent Phenotype ◽  
Ifn Γ

Immunosenescence is a physiological process that is associated with changes in the immune system, particularly among CD8 T-cells. Recent studies have hypothesized that senescent CD8 T-cells are produced with chronologic age by chronic stimulation, leading to the acquisition of hallmarks of innate-like T-cells. While conventional CD8 T-cells are quite well characterized, CD8 T-cells sharing features of NK cells and memory CD8 T-cells, are a newly described immune cell population. They can be distinguished from conventional CD8 T-cells by their combined expression of panKIR/NKG2A and Eomesodermin (E), a unique phenotype closely associated with IFN-γ production in response to innate stimulation. Here, we first provided new evidence in favor of the innate character of panKIR/NKG2A(+) E(+) CD8 T-cells in normal subjects, documenting their position at an intermediate level in the innateness gradient in terms of both innate IFN-γ production and diminished mitochondrial mass. We also revealed that CD8 E(+) panKIR/NKG2A(+) T-cells, hereafter referred to as Innate E(+) CD8 T-cells, exhibit increased senescent (CD27(-) CD28(-)) phenotype, compared to their conventional memory counterparts. Surprisingly, this phenomenon was not dependent on age. Given that inflammation related to chronic viral infection is known to induce NK-like marker expression and a senescence phenotype among CD8 T-cells, we hypothesized that innate E(+) CD8 T-cells will be preferentially associated with exacerbated cellular senescence in response to chronic alloantigen exposure or CMV infection. Accordingly, in a pilot cohort of stable kidney allotransplant recipients, we observed an increased frequency of the Innate E(+) CD8 T-cell subset, together with an exacerbated senescent phenotype. Importantly, this phenotype cannot be explained by age alone, in clear contrast to their conventional memory counterparts. The senescent phenotype in CD8 T-cells was further increased in cytomegalovirus (CMV) positive serology transplant recipients, suggesting that transplantation and CMV, rather than aging by itself, may promote an exacerbated senescent phenotype of innate CD8 T-cells. In conclusion, we proposed that kidney transplantation, via the setting of inflammatory stimuli of alloantigen exposure and CMV infection, may exogenously age the CD8 T-cell compartment, especially its innate component. The physiopathological consequences of this change in the immune system remain to be elucidated.

The Importance of Be(ginn)Ing Naïve: Implications for Cancer Immune-Gene Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2052-2052
Author(s):  
Nicoletta Cieri ◽  
Barbara Camisa ◽  
Fabienne Cocchiarella ◽  
Elena Provasi ◽  
Zulma Magnani ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cell Subset ◽  
T Cell Response ◽  
Immune Gene ◽  
Self Renewal ◽  
T Cell Subset

Abstract Abstract 2052 T cell engineering against tumor antigens aims at ameliorating current immunotherapeutic strategies. To date, however, the suboptimal persistence of the transferred cells represents a serious limitation of this approach. The most appropriate T cell subset to be infused should ensure optimal in vivo persistence and yet appropriate anti-tumor activity. Here we report that culturing highly purified naïve T (TN) cells with beads conjugated to anti-CD3 and anti-CD28 antibodies, allows the retrieval of a novel post-mitotic CD45RA+ CD62L+ CCR7+ T cell population, which requires IL-7 and IL-15 for expansion and maintenance. This population is highly proliferative and sensitive to RV and LV transduction, expresses low levels of γIFN and cytotoxic molecules and is best defined as IL-7Rα+ CXCR4+ c-kit+ CCR5− HLA-DR− PD-1−. When infused in immunodeficient mice, genetically manipulated and in vitro expanded TN proved superior engraftment and longer persistence than transduced central memory (TCM) cells, and xenoreactivity comparable to that of unmanipulated lymphocytes. Engineered TN, but not TCM, maintained engraftment and xenoreactivity in serial transplantation experiments, indicating unique self-renewal abilities. Given the great potentials of this novel TN-derived cell population for immune-gene therapy, we further characterized it by molecular profiling. The gene expression signature is typical of antigen-experienced lymphocytes and classifies these cells between naturally occurring TN and TCM lymphocytes. Because of this and of the self-renewal abilities displayed in vivo, we termed them as precursor to TCM (TpreCM). We next sought to identify the natural counterpart of this TpreCM population in healthy donors, exploiting some of the markers present in the TpreCM signature, such as CD95 which is expressed by all memory T subsets but not by TN, and we selected the pp65 protein of cytomegalovirus (CMV) as a model antigen. CMV persistent infection induces a T-cell response that is maintained throughout life, indicating that a self-renewing memory T cells are generated. We studied the phenotype of CMV pp65-specific CD8+ T cells in seropositive donors and identified antigen-specific CD45RA+CD62L+. Among CD45RA+CD62L+ cells CMV-specific cells were enriched for CD45ROdim and CD95+ lymphocytes, which represent bona fide TpreCM. To functionally characterize natural TpreCM, we sorted CD45RA+CD62L+ cells according to their CD95 expression and challenged them with increasing doses anti-CD3 antibody, with or without a costimulatory signal. We found that among CD45RA+CD62L+ cells, only CD95+ lymphocytes were responsive to TCR-triggering alone, while CD95− cells required costimulation to proliferate. In conclusion, we identified a novel memory T cell subset, and identified conditions able to gene-modify and expand these memory lymphocytes while preserving their functional characteristics. Exploitation of these concepts might improve cancer adoptive immunotherapy. Disclosures: Bonini: MolMed: Consultancy.

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