scholarly journals 781 Validation of the combinatorial effect of blinatumomab and nivolumab in cancer therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A831-A831
Author(s):  
Tienan Wang ◽  
Qing Lin ◽  
Jie Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Culture System ◽  
Cell Activation ◽  
Checkpoint Inhibitors

BackgroundCancer immunotherapies, including immune checkpoint inhibitors, CAR-T, cancer vaccines and bispecific antibodies, have been brought to spot light in recent years as several therapeutic strategies targeting the immune system have produced exciting clinical results. Bispecific antibody typically play dual roles in blocking the immune checkpoint and redirecting/re-boosting the function of the immune effector cells. Blinatumomab belongs to CD3 bispecific T cell engager (CD3 BiTE), which was engineered to harbor two arms binding with CD3 and CD19 simultaneously and direct CD8+ T cells to specifically recognize CD19 positive lymphoma cells to execute cytotoxicity. Approval of Blinatumomab for patients with relapse/refractory B cell acute lymphoblastic leukemia (ALL) has driven remarkable increase in combination studies of Blinatumomab with other immunotherapies such as checkpoint inhibitors.MethodsIn this study, we developed CD8+ T cytotoxic system targeting different B lymphoma cell line and fully validated the function of Blinatumomab in promoting target tumor cell lysis by primary CD8+ T cells (figure 1). In addition, we established a mixed lymphocyte and tumor system to mimic physiological TME to dissect the combinational role of Nivolumab and Blinatumomab (figure 2).ResultsThe result suggest that combinatory therapy is highly depend on the dosage of Blinatumomab and also T cell number in the TME, which might give an instruction for ongoing clinical trial design. Finally, we have employed humanized mouse models bearing Raji or Daudi tumor cells to further validate this combination treatment in vivo. Both In-vivo and In-vitro data support that Blinatumomab is dominant in activing T cell and Nivolumab can only exhibit synergistic effect under suboptimal dosage of Blinatumomab.Abstract 781 Figure 1Establishment of In vitro co-culture system for CD3 BiTEestablish in vitro human PBMC based system to validate CD3 BiTE functionAbstract 781 Figure 2Opdivo and CD3 BiTE CombinationOpdivo could further promote T cell activation under the treatment of CD3 BiTEConclusionsSuccessfully establish in vitro system to evaluate the function of CD3 BiTE and also take advantage of MLR/tumor co-culture system to demonstrate PD1 antibody could further promote T cell activation under appropriate dosage of CD3 BiTE.

scholarly journals 643 Vasoactive intestinal peptide as a novel immune checkpoint molecule in activated T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A672-A672
Author(s):  
Sruthi Ravindranathan ◽  
Tenzin Passang Fnu ◽  
Edmund Waller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vasoactive Intestinal Peptide ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Activated T Cells

BackgroundOnly a fraction of cancer patients responds to current antibody-based immune checkpoint inhibitors.1 Our lab has identified vasoactive intestinal peptide-receptor (VIP-R) signaling as a targetable immune checkpoint pathway in cancer. VIP is a small neuropeptide with known immunosuppressive effects on T cells, in particular, CD4+ T cells.2–5 However, little is known about VIP-R signaling in CD8+ T cells. To define mechanisms by which VIP limits T cell activation and function, we studied the regulation of VIP and VIP receptors (VIP-R) in T cells following their activation in vitro and in mouse models of cancer.MethodsT cells from healthy human donors and murine splenocytes were activated using anti-CD3 coated plates. Western blots measured intracellular pre-pro-VIP, along with its cognate receptors; VPAC1 and VPAC2. Purified cultures of CD4+ and CD8+ T cells were used to interrogate the protein expression on specific T cell subsets. Activation and chemokine receptor expression was assessed by flow cytometry to evaluate T cell response to VIP-R antagonists in vitro and in tumor-bearing mice engrafted with pancreatic cancer cell lines.ResultsBoth murine and human T cells upregulate pre-pro-VIP following TCR stimulation with similar kinetics of VIP receptors between species. VIP expression is upregulated in vivo following treatment of tumor-bearing mice with anti-PD1 MoAb. VIP expression is temporally correlated with the upregulation of other co-inhibitory molecules. VPAC1 expression modestly increased in activated T cells while VPAC2 expression decreased. A non-canonical high molecular weight (HMW) form of VPAC2-related protein robustly and transiently increase in activated T cells. Expression of HMW form of VPAC2 is only detected in activated CD4+ T cells. Of note, activated CD4+ but not CD8+ T cells upregulate pre-pro-VIP. Pharmacological inhibition of VIP-R signaling significantly increased CD69+, OX40+, Lag3+, and PD1+ expression in CD4+ subsets compared to activated T cells without VIP-R antagonists (p < 0.05). In contrast, CD8+ T cells upregulate VPAC1 but not VPAC2 receptor following activation. VIP-R antagonist treatment of activated CD8+ T cells significantly decreased CXCR4+ expression (p < 0.05). CXCR3 and CXCR5 expression were not affected by VIP-R antagonist treatment.ConclusionsVIP-R signaling is a novel immune autocrine and paracrine checkpoint pathway in activated CD4+ T cells. Activated CD4+ and CD8+ T cells demonstrate different kinetics of VPAC1 and VPAC2 expression, suggesting different immune-regulatory responses to VIP-R antagonists. Understanding VIP-R signaling induced during T cell activation can lead to specific drugs that target VIP-R pathways to enhance cancer immunotherapy.AcknowledgementsWe thank healthy volunteers for blood samples. The authors also thank the shared resources at Emory University, namely, Emory Flow Cytometry Core (EFCC) and Integrated Cellular Imaging Core (ICI) and Yerkes Nonhuman Primate Genomics Core that provided services or instruments at subsidized cost to conduct some of the reported experiments. This work was supported in part by Katz Foundation funding, Georgia Research Alliance, and Emory School of Medicine Dean's Imagine, Innovate and Impact (I3) venture award to Edmund K. Waller.ReferencesDarvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Experimental and Molecular Medicine 2018.Wang HY, Jiang XM, Ganea D. The Neuropeptides VIP and PACAP Inhibit IL-2 Transcription by Decreasing c-Jun and Increasing JunB Expression in T Cells. J Neuroimmunol 2000;104(1):68–78.Delgado M. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T Cells in Vivo. J Leukoc Biol 2005.Anderson P, Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Mol Cell Biol 2010.Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids. NIH Public Access July 2013, 25–39.Ethics ApprovalDe-identified blood samples from consented healthy volunteers (IRB 00046063) were obtained with approval from Institutional Review Boards.

scholarly journals CD8+ T Cell Metabolic Rewiring Defined by Single-Cell RNA-Sequencing Identifies a Critical Role of ASNS Expression Dynamics in T Cell Differentiation

2021 ◽  
Author(s):  
Juan Fernandez-Garcia ◽  
Fabien Franco ◽  
Sweta Parik ◽  
Antonino A Pane ◽  
Dorien Broekaert ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Differentiation

Cytotoxic T cells dynamically rewire their metabolism during the course of an immune response. While T cell metabolism has been extensively studied at phenotypic endpoints of activation and differentiation, the underlying dynamics remain largely elusive. Here, we leverage on single-cell RNA-sequencing (scRNA-seq) measurements of in vitro activated and differentiated CD8+ T cells cultured in physiological media to resolve these metabolic dynamics. We find that our scRNA-seq analysis identifies most metabolic changes previously defined in in vivo experiments, such as a rewiring from an oxidative to an anabolism-promoting metabolic program during activation to an effector state, which is later reverted upon memory polarization. Importantly, our scRNA-seq data further provide a dynamic description of these changes. In this sense, our data predict a differential time-dependent reliance of CD8+ T cells on the synthesis versus uptake of various non-essential amino acids during T cell activation, which we corroborate with additional functional in vitro experiments. We further exploit our scRNA-seq data to identify metabolic genes that could potentially dictate the outcome of T cell differentiation, by ranking them based on their expression dynamics. Among the highest-ranked hits, we find asparagine synthetase (Asns), whose expression sharply peaks for effector CD8+ T cells and further decays towards memory polarization. We then confirm that these in vitro Asns expression dynamics are representative of an in vivo situation in a mouse model of viral infection. Moreover, we find that disrupting these expression dynamics in vitro, by depleting asparagine from the culture media, delays central-memory polarization. Accordingly, we find that preventing the decay of ASNS by stable overexpression at the protein level in vivo leads to a significant increase in effector CD8+ T cell expansion, and a concomitant decrease in central-memory formation, in a mouse model of viral infection. This shows that ASNS expression dynamics dictate the fate of CD8+ T cell differentiation. In conclusion, we provide a resource of dynamic expression changes during CD8+ T cell activation and differentiation that is expected to increase our understanding of the dynamic metabolic requirements of T cells progressing along the immune response cascade.

scholarly journals TRPM2 Is Not Required for T-Cell Activation and Differentiation

2022 ◽  
Vol 12 ◽  
Author(s):  
Niels C. Lory ◽  
Mikolaj Nawrocki ◽  
Martina Corazza ◽  
Joanna Schmid ◽  
Valéa Schumacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Activation Markers

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2-/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2-/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2-/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2-/- mice and after transfer of WT and Trpm2-/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2-/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.

scholarly journals 702 TJ-CD4B (ABL111), a Claudin18.2-targeted 4-1BB tumor engager induces potent tumor-dependent immune response without dose-limiting toxicity in preclinical studies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A730-A730
Author(s):  
Wenqing Jiang ◽  
Zhengyi Wang ◽  
Zhen Sheng ◽  
Jaeho Jung ◽  
Taylor Guo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Gene Expression Analysis ◽  
Cell Activation ◽  
Clinical Development ◽  
Cynomolgus Monkeys ◽  
Anti Tumor Activity

Background4-1BB (CD137) is a co-stimulatory receptor that stimulates the function of multiple immune cells. Its ability to induce potent anti-tumor activity makes 4-1BB an attractive target for immuno-oncology. However, clinical development of a monospecific 4-1BB agonistic antibody has been hampered by dose-limiting hepatic toxicities. To minimize systemic toxicities, we have developed a novel Claudin18.2 (CLDN18.2) x 4-1BB bispecific antibody, TJ-CD4B (ABL111) that stimulates 4-1BB pathway only when it engages with Claudin 18.2, a tumor-associated antigen specifically expressed in gastrointestinal cancers. TJ-CD4B (ABL111) is now being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT04900818).MethodsTJ-CD4B (ABL111) was evaluated in vivo using the human 4-1BB knock-in mice bearing CLDN18.2 expressing MC38 tumor cells. Pharmacodynamic effects upon treatment were characterized in tumor tissue and blood. Immunophenotyping of the tumor microenvironment (TME) and peripheral blood was performed by flow cytometry. Soluble biomarkers were measured using Luminex-based multiplex assay. In-depth gene expression analysis was performed on primary human CD8+ T cells that were co-cultured with CLDN18.2 expressing cells in the presence of anti-CD3 using NanoString nCounter®. Pharmacokinetic (PK) and toxicity study were performed in cynomolgus monkeys.ResultsTJ-CD4B (ABL111) elicited complete tumor regression in 13 out of 18 MC38 tumor bearing mice given at a dose above 2 mg/kg. Dose-dependent anti-tumor activity was associated with enhanced T cell activation in TME and expansion of memory T cells in the peripheral blood. Increased CD8+ T cells number and proliferation were observed in both tumor nest and surrounding stroma while the level of soluble 4-1BB in the serum was also elevated in response to the treatment. In vitro gene expression analysis by Nanostring revealed TJ-CD4B(ABL111) effectively activated immune pathways characterized by IFN?-signaling and T cell inflammation. Preclinically, TJ-CD4B was well tolerated at the repeated doses up to 100 mg/kg/wk in cynomolgus monkeys without the adverse influence on the liver function which is generally affected by 4-1BB activation. Besides, no cytokine release or immune activation was observed in the periphery.ConclusionsTJ-CD4B (ABL111) is a novel CLDN18.2 dependent 4-1BB bispecific agonist antibody that induced T cell activation and memory response in tumor with CLDN18.2 expression, leading to a strong anti-tumor activity in vivo. TJ-CD4B did not induce systemic immune response nor hepatic toxicity due to the CLDN18.2 dependent 4-1BB stimulation. These data warrant the current clinical development in phase I trial to validate the safety properties and tumor specific responses.

scholarly journals Modulating p56Lck in T-Cells by a Chimeric Peptide Comprising Two Functionally Different Motifs of Tip fromHerpesvirus saimiri

2015 ◽  
Vol 2015 ◽  
pp. 1-12
Author(s):  
Jean-Paul Vernot ◽  
Ana María Perdomo-Arciniegas ◽  
Luis Alberto Pérez-Quintero ◽  
Diego Fernando Martínez
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lipid Rafts ◽  
T Cell Activation ◽  
Cell Activation ◽  
Jurkat Cells ◽  
Chimeric Peptide ◽  
Vector Targeting

The Lck interacting protein Tip ofHerpesvirus saimiriis responsible for T-cell transformation bothin vitroandin vivo. Here we designed the chimeric peptide hTip-CSKH, comprising the Lck specific interacting motif CSKH of Tip and its hydrophobic transmembrane sequence (hTip), the latter as a vector targeting lipid rafts. We found that hTip-CSKH can induce a fivefold increase in proliferation of human andAotussp. T-cells. Costimulation with PMA did not enhance this proliferation rate, suggesting that hTip-CSKH is sufficient and independent of further PKC stimulation. We also found that human Lck phosphorylation was increased earlier after stimulation when T-cells were incubated previously with hTip-CSKH, supporting a strong signalling and proliferative effect of the chimeric peptide. Additionally, Lck downstream signalling was evident with hTip-CSKH but not with control peptides. Importantly, hTip-CSKH could be identified in heavy lipid rafts membrane fractions, a compartment where important T-cell signalling molecules (LAT, Ras, and Lck) are present during T-cell activation. Interestingly, hTip-CSKH was inhibitory to Jurkat cells, in total agreement with the different signalling pathways and activation requirements of this leukemic cell line. These results provide the basis for the development of new compounds capable of modulating therapeutic targets present in lipid rafts.

scholarly journals IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Marie-Line Puiffe ◽  
Aurélie Dupont ◽  
Nouhoum Sako ◽  
Jérôme Gatineau ◽  
José L. Cohen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cell Clone ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Clone

IL4I1 is an immunoregulatory enzyme that inhibits CD8 T-cell proliferation in vitro and in the tumoral context. Here, we dissected the effect of IL4I1 on CD8 T-cell priming by studying the differentiation of a transgenic CD8 T-cell clone and the endogenous repertoire in a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. Unexpectedly, we show that IL4I1 accelerates the expansion of functional effector CD8 T cells during the first several days after infection and increases the average affinity of the elicited repertoire, supporting more efficient LCMV clearance in WT mice than IL4I1-deficient mice. Conversely, IL4I1 restrains the differentiation of CD8 T-cells into long-lived memory precursors and favors the memory response to the most immunodominant peptides. IL4I1 expression does not affect the phenotype or antigen-presenting functions of dendritic cells (DCs), but directly reduces the stability of T-DC immune synapses in vitro, thus dampening T-cell activation. Overall, our results support a model in which IL4I1 increases the threshold of T-cell activation, indirectly promoting the priming of high-affinity clones while limiting memory T-cell differentiation.

scholarly journals Tumor masses support naive T cell infiltration, activation, and differentiation into effectors

2010 ◽  
Vol 207 (8) ◽  
pp. 1791-1804 ◽  
Author(s):  
Elizabeth D. Thompson ◽  
Hilda L. Enriquez ◽  
Yang-Xin Fu ◽  
Victor H. Engelhard
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cell Activation ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration

Studies of T cell responses to tumors have focused on the draining lymph node (LN) as the site of activation. We examined the tumor mass as a potential site of activation after adoptive transfer of naive tumor-specific CD8 T cells. Activated CD8 T cells were present in tumors within 24 h of adoptive transfer and proliferation of these cells was also evident 4–5 d later in mice treated with FTY720 to prevent infiltration of cells activated in LNs. To confirm that activation of these T cells occurred in the tumor and not the tumor-draining LNs, we used mice lacking LNs. Activated and proliferating tumor-infiltrating lymphocytes were evident in these mice 24 h and 4 d after naive cell transfer. T cells activated within tumors acquired effector function that was evident both ex vivo and in vivo. Both cross-presenting antigen presenting cells within the tumor and tumor cells directly presenting antigen activated these functional CD8 effectors. We conclude that tumors support the infiltration, activation, and effector differentiation of naive CD8 T cells, despite the presence of immunosuppressive mechanisms. Thus, targeting of T cell activation to tumors may present a tool in the development of cancer immunotherapy.

T cell-T cell activation in multiple sclerosis

1997 ◽  
Vol 3 (4) ◽  
pp. 238-242 ◽  
Author(s):  
JW Lindsey ◽  
RH Kerman ◽  
JS Wolinsky
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Activated T Cells ◽  
In Vitro Proliferation

Activated T cells are able to stimulate proliferation in resting T cells through an antigen non-specific mechanism. The in vivo usefulness of this T cell-T cell activation is unclear, but it may serve to amplify immune responses. T cell-T cell activation could be involved in the well-documented occurrence of multiple sclerosis (MS) exacerbations following viral infections. Excessive activation via this pathway could also be a factor in the etiology of MS. We tested the hypothesis that excessive T cell-T cell activation occurs in MS patients using in vitro proliferation assays comparing T cells from MS patients to T cells from controls. When tested as responder cells, T cells from MS patients proliferated slightly less after stimulation with previously activated cells than T cells from controls. When tested as stimulator cells, activated cells from MS patients stimulated slightly more non-specific proliferation than activated cells from controls. Neither of these differences were statistically significant We conclude that T cell proliferation in response to activated T cells is similar in MS and controls.

scholarly journals Signaling function of PRC2 is essential for TCR-driven T cell responses

2018 ◽  
Vol 215 (4) ◽  
pp. 1101-1113 ◽  
Author(s):  
Marc-Werner Dobenecker ◽  
Joon Seok Park ◽  
Jonas Marcello ◽  
Michael T. McCabe ◽  
Richard Gregory ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Polycomb Repressive Complex 2 ◽  
Histone Lysine Methyltransferases

Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)–mediated signaling. We show that short-term suppression of PRC2 precludes TCR-driven T cell activation in vitro. We also demonstrate that pharmacological inhibition of PRC2 in vivo greatly attenuates the severe T cell–driven autoimmunity caused by regulatory T cell depletion. Our data reveal cytoplasmic PRC2 is one of the most potent regulators of T cell activation and point toward the therapeutic potential of PRC2 inhibitors for the treatment of T cell–driven autoimmune diseases.

scholarly journals Cd2 Sets Quantitative Thresholds in T Cell Activation

1999 ◽  
Vol 190 (10) ◽  
pp. 1383-1392 ◽  
Author(s):  
Martin F. Bachmann ◽  
Marijke Barner ◽  
Manfred Kopf
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Dose Response ◽  
Response Curve ◽  
Cell Activation ◽  
Dose Response Curve ◽  
Lymphocyte Function

It has been proposed that CD2, which is highly expressed on T cells, serves to enhance T cell–antigen presenting cell (APC) adhesion and costimulate T cell activation. Here we analyzed the role of CD2 using CD2-deficient mice crossed with transgenic mice expressing a T cell receptor specific for lymphocytic choriomeningitis virus (LCMV)-derived peptide p33. We found that absence of CD2 on T cells shifted the p33-specific dose–response curve in vitro by a factor of 3–10. In comparison, stimulation of T cells in the absence of lymphocyte function–associated antigen (LFA)-1–intercellular adhesion molecule (ICAM)-1 interaction shifted the dose–response curve by a factor of 10, whereas absence of both CD2–CD48 and LFA-1–ICAM-1 interactions shifted the response by a factor of ∼100. This indicates that CD2 and LFA-1 facilitate T cell activation additively. T cell activation at low antigen density was blocked at its very first steps, as T cell APC conjugate formation, TCR triggering, and Ca2+ fluxes were affected by the absence of CD2. In vivo, LCMV-specific, CD2-deficient T cells proliferated normally upon infection with live virus but responded in a reduced fashion upon cross-priming. Thus, CD2 sets quantitative thresholds and fine-tunes T cell activation both in vitro and in vivo.

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