scholarly journals Antigen-dependent and -independent Ca2+ Responses Triggered in T Cells by Dendritic Cells Compared with B Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1473-1484 ◽  
Author(s):  
Jérôme Delon ◽  
Nadège Bercovici ◽  
Graça Raposo ◽  
Roland Liblau ◽  
Alain Trautmann
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Mhc Class Ii ◽  
Ex Vivo ◽  
Cell Formation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Survival Signal

Dendritic cells (DCs) are much more potent antigen (Ag)-presenting cells than resting B cells for the activation of naive T cells. The mechanisms underlying this difference have been analyzed under conditions where ex vivo DCs or B cells presented known numbers of specific Ag–major histocompatibility complex (MHC) complexes to naive CD4+ T cells from T cell antigen receptor (TCR) transgenic mice. Several hundred Ag–MHC complexes presented by B cells were necessary to elicit the formation of a few T–B conjugates with small contact zones, and the resulting individual T cell Ca2+ responses were all-or-none. In contrast, Ag-specific T cell Ca2+ responses can be triggered by DCs bearing an average of 30 Ag–MHC complexes per cell. Formation of T–DC conjugates is Ag-independent, but in the presence of the Ag, the surface of the contact zone increases and so does the amplitude of the T cell Ca2+ responses. These results suggest that Ag is better recognized by T cells on DCs essentially because T–DC adhesion precedes Ag recognition, whereas T–B adhesion requires Ag recognition. Surprisingly, we also recorded small Ca2+ responses in T cells interacting with unpulsed DCs. Using DCs purified from MHC class II knockout mice, we provide evidence that this signal is mostly due to MHC–TCR interactions. Such an Ag-independent, MHC-triggered calcium response could be a survival signal that DCs but not B cells are able to deliver to naive T cells.

ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 216-223 ◽  
Author(s):  
Elodie Segura ◽  
Carole Nicco ◽  
Bérangère Lombard ◽  
Philippe Véron ◽  
Graça Raposo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Responses ◽  
Class Ii ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Responses

Exosomes are secreted vesicles formed in late endocytic compartments. Immature dendritic cells (DCs) secrete exosomes, which transfer functional major histocompatibility complex (MHC)–peptide complexes to other DCs. Since immature and mature DCs induce different functional T-cell responses (ie, tolerance versus priming), we asked whether DC maturation also influenced the priming abilities of their exosomes. We show that exosomes secreted by lipopolysaccharide (LPS)–treated mature DCs are 50- to 100-fold more potent to induce antigen-specific T-cell activation in vitro than exosomes from immature DCs. In vitro, exosomes from mature DCs transfer to B lymphocytes the ability to prime naive T cells. In vivo, only mature exosomes trigger effector T-cell responses, leading to fast skin graft rejection. Proteomic and biochemical analyses revealed that mature exosomes are enriched in MHC class II, B7.2, intercellular adhesion molecule 1 (ICAM-1), and bear little milk-fat globule–epidermal growth factor–factor VIII (MFG-E8) as compared with immature exosomes. Functional analysis using DC-derived exosomes from knock-out mice showed that MHC class II and ICAM-1 are required for mature exosomes to prime naive T cells, whereas B7.2 and MFG-E8 are dispensable. Therefore, changes in protein composition and priming abilities of exosomes reflect the maturation signals received by DCs.

scholarly journals Freshly Isolated Peyer's Patch, but Not Spleen, Dendritic Cells Produce Interleukin 10 and Induce the Differentiation of T Helper Type 2 Cells

1999 ◽  
Vol 190 (2) ◽  
pp. 229-240 ◽  
Author(s):  
Akiko Iwasaki ◽  
Brian Lee Kelsall
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Ex Vivo ◽  
T Helper ◽  
Phenotypic Analysis ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Ifn Γ

Orally administered antigens often generate immune responses that are distinct from those injected systemically. The role of antigen-presenting cells in determining the type of T helper cell response induced at mucosal versus systemic sites is unclear. Here we examine the phenotypic and functional differences between dendritic cells (DCs) freshly isolated from Peyer's patches (PP) and spleen (SP). Surface phenotypic analysis of CD11c+ DC populations revealed that PP DCs expressed higher levels of major histocompatibility complex class II molecules, but similar levels of costimulatory molecules and adhesion molecules compared with SP DCs. Freshly isolated, flow cytometrically sorted 98–100% pure CD11c+ DC populations from PP and SP were compared for their ability to stimulate naive T cells. First, PP DCs were found to be much more potent in stimulating allogeneic T cell proliferation compared with SP DCs. Second, by using naive T cells from ovalbumin peptide–specific T cell receptor transgenic mice, these ex vivo DCs derived from PP, but not from SP, were found to prime for the production of interleukin (IL)-4 and IL-10 (Th2 cytokines). In addition, PP DCs were found to prime T cells for the production of much lower levels of interferon (IFN)-γ (Th1) compared with SP DCs. The presence of neutralizing antibody against IL-10 in the priming culture dramatically enhanced IFN-γ production by T cells stimulated with PP DCs. Furthermore, stimulation of freshly isolated PP DCs via the CD40 molecule resulted in secretion of high levels of IL-10, whereas the same stimulus induced no IL-10 secretion from SP DCs. These results suggest that DCs residing in different tissues are capable of inducing distinct immune responses and that this may be related to the distinct cytokines produced by the DCs from these tissues.

scholarly journals Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

1992 ◽  
Vol 176 (5) ◽  
pp. 1431-1437 ◽  
Author(s):  
M Croft ◽  
D D Duncan ◽  
S L Swain
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 Cells ◽  
Peptide Antigen ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

Steady-state dendritic cells expressing cognate antigen terminate memory CD8+ T-cell responses

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2091-2100 ◽  
Author(s):  
Tony J. Kenna ◽  
Ranjeny Thomas ◽  
Raymond J. Steptoe
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Steady State ◽  
T Cell ◽  
Developmental Plasticity ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cognate Antigen ◽  
Costimulatory Signals

Antigen stimulation of naive T cells in conjunction with strong costimulatory signals elicits the generation of effector and memory populations. Such terminal differentiation transforms naive T cells capable of differentiating along several terminal pathways in response to pertinent environmental cues into cells that have lost developmental plasticity and exhibit heightened responsiveness. Because these cells exhibit little or no need for the strong costimulatory signals required for full activation of naive T cells, it is generally considered memory and effector T cells are released from the capacity to be inactivated. Here, we show that steady-state dendritic cells constitutively presenting an endogenously expressed antigen inactivate fully differentiated memory and effector CD8+ T cells in vivo through deletion and inactivation. These findings indicate that fully differentiated effector and memory T cells exhibit a previously unappreciated level of plasticity and provide insight into how memory and effector T-cell populations may be regulated.

A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2801-2809 ◽  
Author(s):  
Matthias Gunzer ◽  
Carsten Weishaupt ◽  
Anja Hillmer ◽  
Yasmin Basoglu ◽  
Peter Friedl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presenting Cells ◽  
Model Systems ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting ◽  
Activated B Cells

Abstract For activation T cells engage antigen-presenting cells (APCs) in lymphatic tissues. The contact duration and kinetics (static versus dynamic) vary considerably in different model systems; however, it is unclear whether T cells, APCs, or the environment are responsible for the observed discrepancies. Using 3-D collagen matrices as structural scaffold, we directly compared the kinetics of T-cell engagement and activation by functionally major APC types, ie, dendritic cells (DCs) and resting or activated B cells. Resting B cells engaged T cells in long-lived (several hours), adhesive, and leukocyte function-associated antigen-1 (LFA-1)-dependent conjugates in 3-D collagen as well as in intact lymph nodes in vivo. DCs and preactivated B cells, however, supported predominantly dynamic, short-lived (minutes), and sequential contacts to T cells that were dependent on high cytoskeletal activity of the APCs but could not be inhibited by anti-LFA-1 treatment. Naive T cells were most strongly activated by DCs and activated B cells, whereas resting B cells were 100-fold less efficient to induce T-cell proliferation. Thus, in the same 3-D environment, naive T cells respond with a spectrum of different interaction modes dependent on the type and activation state of the APCs. Thereby, more dynamic interaction kinetics is positively correlated with higher T-cell priming efficiency. (Blood. 2004;104: 2801-2809)

scholarly journals B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes.

1993 ◽  
Vol 177 (3) ◽  
pp. 679-690 ◽  
Author(s):  
F Ronchese ◽  
B Hausmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Scid Mice ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Responses

The ability of B cells or macrophages and dendritic cells (DC) to elicit class II-restricted T cell responses in vivo was compared using a mouse chimera model. Severe combined immunodeficient (SCID) mice (H-2d), reconstituted either with T or T+B lymphocytes from (H-2d x H-2b) donors, were immunized subcutaneously with protein antigen (Ag) to induce a class II-restricted T cell response. The frequency and major histocompatibility complex restriction of the resulting Ag-specific T cells were analyzed to establish whether B cells were necessary for the induction of class II-restricted T cell responses, and to determine the cell type on which priming had occurred. The results indicated that: (a) B cells are not necessary for the induction of a class II-restricted T cell response in vivo, as the frequencies of interleukin 2 (IL-2)- or IL-3-secreting T cells induced in the presence or absence of B cells were comparable. (b) Activation of naive T cells requires presentation of Ag on DC; Ag presented only on B cells is not sufficient to elicit a response. No H-2b-restricted, IL-3-secreting cells could in fact be detected in SCID mice reconstituted with naive (H-2d x H-2b) T cells and nonimmune or antigen-primed (H-2d x H-2b) B cells. (c) Previously primed T cells are able to be stimulated by Ag presented by both B cells and DC. H-2b-restricted, IL-3-secreting cells could in fact be readily demonstrated in SCID mice reconstituted with antigen-primed (H-2d x H-2b) T and B cells. Irrespective of whether the T cells were naive or previously activated, B cells were able to respond with an Ag-specific immunoglobulin G response, indicating that B cells were functional and able to present Ag in order to receive specific T cell help. Therefore, it appears that B cells are not necessary and do not participate in the initial priming of T cells; however, Ag presented by B cells can reactivate previously primed T cells. Taken together, these data indicate that during the course of an immune response Ag is first presented to naive T cells via DC, and only subsequently primed T cells can be stimulated by Ag presented by B cells.

scholarly journals Blinatumomab-Induced T Cell Activation at Single Cell Transcriptome Resolution

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3886-3886
Author(s):  
Hong Yin ◽  
Yi Huo ◽  
Zhen Sheng ◽  
Chi-Ming Li ◽  
Daniel C Ellwanger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Target Cells ◽  
Ex Vivo Model ◽  
Naive T Cells ◽  
Naïve T Cells

Introduction Blinatumomab, a bi-specific T cell engager (BiTE®) combining the VH and VL domains of two antibodies against human CD19 and CD3, has been approved by U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory B precursor ALL (r/r B-ALL) for its clinical benefit demonstrated in different clinical trials. Clinical trials have also shown that there are still patients refractory to blinatumomab. It is thus important to understand the resistance mechanisms. Blinatumomab connects patients' autologous T cells and target cells to form immunologic synapse which potently triggers the activation signaling cascades in T cells and guides T cells to recognize and induce perforin/granzyme-mediated lysis of CD19+ B-ALL cells. Previous studies showed blinatumomab-mediated cytotoxicity involves different T cell subpopulations. But response of each T cell subpopulation to blinatumomab treatment remained largely unknown. Methods and Results In this study, we used 10X Genomics based single cell RNA sequencing to analyze the transcriptome of single T cells before and after blinatumomab treatment. First, ex vivo blinatumomab cytotoxicity model was established, in which healthy PBMCs were used as effector cells and cocultured with target cells (RS4;11 cells or SUP-B15 cells) at an effector-to-target cell ratio of 10:1 with 0.1 ng/mL blinatumomab. Then, PBMCs and BMMCs from 2 B-ALL patients were cultured with 10 ng/mL blinatumomab. Cells from both ex vivo model and patient samples were sequenced using 10X Genomics platform. In total, transcriptome of 17920 single T cells from the ex vivo model and 2271 single T cells from patient sample were analyzed. Based on T cell trajectory analysis, we identified four distinct populations of blinatumomab-activated T cells, which were derived from CD8+ effector memory T (TEM) cells, CD4+ central memory (TCM) cells, naïve T cells and Tregs, respectively. The differentially expressed genes in activated clusters were analyzed to reflect T cell activation mechanisms. The result showed blinatumomab induced the upregulation of aerobic glycolysis pathway (PKM, PGAM1, ENO1, GAPDH and LDHA), cytoskeleton dynamics pathway (ACTD1, ACTB, NME1 and TUBA1B), IFN-responsive pathway (GBP1, PSME2, WARS, CXCL10 and STAT1), and the upregulation of well-known immune-related genes (TNFRSF4, TNFRSF18, LAG3, CD69, IL2RA, MIR155HG, BATF, SH2D2A, LTA, NFKBIA and NDFIP2). We found blinatumomab-activated CD8+ TEM cells showed stronger cytotoxic capability than other activated populations with specific production of cytotoxic factors (PRF1, IFNG and FASLG) and cytokines (CCL2, CCL3, CCL3L1, CCL4, CCL4L2, CCL8, XCL1, XCL2, TNFSF9 and TNFSF14). Last, differential gene expression analysis revealed that co-stimulatory (TNFRSF4,TNFRSF9 and TNFRSF18) and co-inhibitory receptors (LAG3 and TIGIT) were similarly up-regulated in clusters activated from memory and naïve T cells, indicating ligand dependent T cell functional outcomes induced by blinatumomab. Conclusion In summary, we used single cell sequencing to map the blinatumomab-mediated T cell activation state transition and reveal the molecular changes in different T cell subpopulations. Memory T cells, naïve T cells and Tregs were identified functional populations after blinatumomab treatment. CD8+ TEM accounted for the majority of blinatumomab-induced cytotoxicity. Furthermore, T cell co-regulatory receptors were identified as potential targets accountable for blinatumomab sensitivity or resistance mechanisms. The study demonstrated that the collected cellular transcriptional profiles can serve as resource to explore novel strategies to enhance the efficacy of blinatumomab. Disclosures Yin: Amgen: Employment. Huo:Amgen: Employment. Sheng:Amgen: Employment. Li:Amgen: Employment. Ellwanger:Amgen: Employment. Lu:Amgen: Employment. Homann:Amgen: Employment. Wang:Amgen: Employment. Ren:Ruijin hospital: Employment.

scholarly journals Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8+ T-cell effector differentiation

2014 ◽  
Vol 112 (2) ◽  
pp. 512-517 ◽  
Author(s):  
Jernej Godec ◽  
Glenn S. Cowley ◽  
R. Anthony Barnitz ◽  
Ozan Alkan ◽  
David E. Root ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Viral Vectors ◽  
Ex Vivo ◽  
Experimental System ◽  
Gene Knockdown ◽  
Naive T Cells ◽  
Naïve T Cells

The differentiation of effector CD8+ T cells is critical for the development of protective responses to pathogens and for effective vaccines. In the first few hours after activation, naive CD8+ T cells initiate a transcriptional program that leads to the formation of effector and memory T cells, but the regulation of this process is poorly understood. Investigating the role of specific transcription factors (TFs) in determining CD8+ effector T-cell fate by gene knockdown with RNAi is challenging because naive T cells are refractory to transduction with viral vectors without extensive ex vivo stimulation, which obscures the earliest events in effector differentiation. To overcome this obstacle, we developed a novel strategy to test the function of genes in naive CD8+ T cells in vivo by creating bone marrow chimera from hematopoietic progenitors transduced with an inducible shRNA construct. Following hematopoietic reconstitution, this approach allowed inducible in vivo gene knockdown in any cell type that developed from this transduced progenitor pool. We demonstrated that lentivirus-transduced progenitor cells could reconstitute normal hematopoiesis and develop into naive CD8+ T cells that were indistinguishable from wild-type naive T cells. This experimental system enabled induction of efficient gene knockdown in vivo without subsequent manipulation. We applied this strategy to show that the TF BATF is essential for initial commitment of naive CD8+ T cells to effector development but becomes dispensable by 72h. This approach makes possible the study of gene function in vivo in unperturbed cells of hematopoietic origin that are refractory to viral transduction.

scholarly journals T-cell mediated anti-tumor immunity after photodynamic therapy: why does it not always work and how can we improve it?

2015 ◽  
Vol 14 (8) ◽  
pp. 1492-1509 ◽  
Author(s):  
Florian Anzengruber ◽  
Pinar Avci ◽  
Lucas Freitas de Freitas ◽  
Michael R. Hamblin
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Photodynamic Therapy ◽  
T Cell ◽  
Lymph Nodes ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Naive T Cells ◽  
Naïve T Cells

Anti-tumor PDT liberates antigens that are taken up by dendritic cells that migrate to lymph nodes, prime naïve T-cells that proliferate and return to destroy remaining tumor cells.

A Short CD3/CD28 Costimulation Combined with IL-21 Enhance the Generation of Human Memory Stem T Cells for Adoptive Immunotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5424-5424 ◽  
Author(s):  
Carmen Alvarez-Fernandez ◽  
Laura Escribà-Garcia ◽  
Jorge Sierra ◽  
Javier Briones
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Ex Vivo ◽  
Culture Period ◽  
Cell Subpopulation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cd28 Costimulation

Abstract Introduction: Adoptive transfer of gene modified T cells (ACT) with chimeric antigen receptors (CARs) is becoming a clinically relevant immunotherapy approach for cancer treatment. One important question involves the selection of the T cell subpopulation for gene-modified ACT. Recent preclinical studies have shown that memory stem T cells (TSCM) (with a phenotype CD45RO-, CD45RA+, CCR7+, CD62L+, CD95+) have higher in vivo persistence, self-renewal, proliferative and antitumor capacities compared to other memory and effector T cell subpopulations. For these reasons, TSCM may represent an ideal candidate for ACT with CARs. Ex vivo generation of TSCM rely on CD3/CD28 costimulation and the use of cytokines such as IL-7 and IL-15 during the entire culture period. However, a strong costimulation may induce differentiation of TSCM to effector memory T cells. In this study, we have analyzed the impact of the costimulation length and the addition of the IL-21 on the ex vivo generation of TSCM cells. Methods: Purified naïve T cells from healthy donors were cultured in the presence of anti-CD3/CD28 coated beads, IL-7, IL-15 and/or IL-21 (25ng/ml). T cells phenotype from the different memory (TCM, TSCM and TEM) and effector subpopulations were analyzed by multiparametric flow cytometry. Particularly, TSCM were identified by a specific plotting strategy. Briefly, CD4+ and CD8+ cells were gated and a CCR7 against CD45RO plot were used to select CCR7+ CD45RO- cells in each subpopulation. Within these cells, a CCR7+ CD45RO- CD45RA+ cell population was identified by plotting CCR7 against CD45RA. Then, CD27 was used to detect CCR7+ CD45RO- CD45RA+ CD27+ cells. Finally, a plot of CD95 against CCR7 was used to identify the CCR7+ CD45RO- CD45RA+ CD27+ CD95+ cell population. Cellular proliferation was analyzed by flow cytometry using CFSE. Results: A short (48 hours) anti-CD3/CD28 costimulation of naïve T cells combined with IL-7 and IL-15 significantly increased the frequencies of CD4+ and CD8+ TSCMex vivo, compared to a long (10 days) costimulation (34.6%±4.4% vs 15.6%±4.24% for CD4+; p=0.008, and 20.5%±4.00% vs 7.7%±2.53% for CD8+; p=0.02). Moreover, the addition of IL-21 to this condition further enhanced the enrichment (47.9%±4.1% vs 34.6%±4.4% for CD4+; p=0.006, and 34.1%±3.5% vs 20.5%±4% for CD8+; p<0.0005) and expansion of CD4+ and CD8+ TSCM, with an increase in absolute numbers (311.3±39 vs 192.8±58.6 fold expansion in CD4+; p=0.04, and 728.1±53 vs 442.7±122 fold expansion in CD8+; p=0.04). In addition, IL-21 did not preferentially enriched for the CD8+ population since the CD4+ TSCM were maintained over the cell culture period in all the conditions tested (CD4+/CD8+ TSCM ratio:1.03±0.28 vs 1.34±0.19 for long costimulation versus long + IL-21, and 0.68±0.14 vs 0.72±0.002 for short vs short + IL-21; p=0.23). Conclusion: We show that these refined in vitro conditions significantly increase the frequencies and expansion of TSCM. Since the reagents used are available in a clinical grade setting, these data may have relevant clinical implications for the generation of this memory T cell subset for adoptive cell therapy with CAR-T cells of patients with cancer. Disclosures No relevant conflicts of interest to declare.

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