scholarly journals TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

2017 ◽  
Vol 199 (12) ◽  
pp. 4091-4102 ◽  
Author(s):  
Nina Chi Sabins ◽  
Olesya Chornoguz ◽  
Karen Leander ◽  
Fred Kaplan ◽  
Richard Carter ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Differentiation ◽  
Effector Memory ◽  
Memory T Cell

scholarly journals Tracking Effector T Cell Dynamics and Immune Inhibitory Receptors in Patients with Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3849-3849
Author(s):  
Hanna A. Knaus ◽  
Raúl Montiel-Esparza ◽  
Joshua F. Zeidner ◽  
Amanda Blackford ◽  
Christopher G. Kanakry ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Expression Patterns ◽  
T Cell Differentiation ◽  
Effector Memory ◽  
Inhibitory Receptors ◽  
Cell Dynamics ◽  
Effector T Cell

Abstract Background: Targeting specific immune inhibitory receptors (iRs) with monoclonal antibodies has led to paradigm-shifting treatment practices in a variety of solid cancers. These advances were in part driven by tremendous progress in phenotypic and functional characterization of altered iR expression patterns and memory T cell differentiation states such as exhaustion and senescence. Effector T cell dynamics and iR expression patterns in AML patients (pts) at diagnosis and after induction chemotherapy are not well understood and, if deciphered, are poised to be critically important for optimal integration of therapeutic blockade of various iRs in the clinic. Methods: We analyzed T cell dynamics and iR expression in peripheral blood (PB, n=45) and bone marrow (BM, n=38) cells from 49 pts (median age 60, range 21-76) with newly diagnosed AML. After induction, 36 (73%) pts entered complete remission (CR) whereas 13 (27%) were non responders (NR). Samples were collected at diagnosis, upon recovery after induction and following consolidation/salvage chemotherapy. Using multi-parameter flow cytometry, we characterized the differentiation status (CD45RA, CCR7), and the expression of co-stimulatory receptors (CD27, CD28) and iRs. Our gating strategy excluded NK T cells (CD3+ CD56+) from downstream analyses. Co-expression of iRs was analyzed in combination of 3 (2B4, BTLA, TIM3) or 4 (KLRG-1, CD57, PD-1 and CD160) markers. As a control, we used PB (n=41)/BM (n=16) lymphocytes from healthy controls (HC). Percentage of cells expressing specific markers were log transformed and modeled with mixed-effect linear regression models. Differential response outcomes over time were tested with interaction terms. Co-expression of multiple iRs was also analyzed with SPICE software version 5.3. Results: At diagnosis, AML pts showed significantly lower median frequency of CD8+ naïve (CD45RA+ CCR7+) T cells in PB, but higher frequencies of terminal differentiated effector memory (TEMRA; CD45RA+ CCR7-) and phenotypically senescent CD8+ CD27- CD28- CD57+ T cells. Significantly higher percentages of PB CD4+ and CD8+ T cells were found to express PD1 and 2B4 compared to HC. Additionally, the frequency of PB CD8+ T cells co-expressing 2-4 iRs was significantly higher in the PB of AML pts (Fig.1). Surprisingly, in contrast to PB, the only significant finding in the BM of AML pts at diagnosis was increased frequency of CD8+ CD27- CD28- CD57+ T cells (p<0.001) compared to HC. At the time of hematopoietic recovery from chemotherapy, TEMRAs and CD8+ CD27- CD28- CD57+ T cells significantly decreased in PB and BM of AML pts, compared to pretreatment levels. However, if analyzed by response, frequencies of these populations declined only in CR pts (p<0.001), but remained unchanged in NR pts. Analysis of iR co-expression in relation to the response to chemotherapy and time revealed that the frequency of CD8+ T cells co-expressing multiple IRs decreases in CR pts but increases in NR pts. These response-associated changes in iR co-expression were observed only in BM while, in PB, the iR co-expression profile remained unchanged irrespective of response. Finally, we assessed the effect of diverse pre-treatment factors on T cell composition at AML diagnosis. We found that older age was associated with increased frequency of CD8+ T cells expressing the iR marker KLRG-1 and the senescent T cell phenotype CD8+ CD27- CD28- CD57+ (p<0.001) but age did not affect iR co-expression on T cells in either PB or BM. CMV seropositivity was associated with increased CD8+ TEMRAs in PB and CD8+ T cells co-expressing multiple iRs (mostly Tim3 and 2B4) in both compartments. The effect of sex, cytogenetic risk group, or ELN category was insignificant. Conclusion: Our study provides critical insights into T cell differentiation and iR expression at diagnosis and during the course of treatment in pts with AML. We have identified several dominant expression patterns suggesting that iR signatures are consistent with immune recognition of AML and their role in sculpting the effector T cell responses directed against AML cell populations. However, data need to be interpreted in the context of the anatomical compartment and non-inheritable variables such as CMV and age. While ongoing work is focused on the deciphering significance of IRs expression for the interpretation of T cell functionality, our data support the rationale for therapeutic blocking of iRs in AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation

2018 ◽  
Vol 215 (9) ◽  
pp. 2429-2443 ◽  
Author(s):  
Mark D. Singh ◽  
Minjian Ni ◽  
Jenna M. Sullivan ◽  
Jessica A. Hamerman ◽  
Daniel J. Campbell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Pi3k Signaling ◽  
Memory T Cell

CD8+ T cells respond to signals via the T cell receptor (TCR), costimulatory molecules, and immunoregulatory cytokines by developing into diverse populations of effector and memory cells. The relative strength of phosphoinositide 3-kinase (PI3K) signaling early in the T cell response can dramatically influence downstream effector and memory T cell differentiation. We show that initial PI3K signaling during T cell activation results in up-regulation of the signaling scaffold B cell adaptor for PI3K (BCAP), which further potentiates PI3K signaling and promotes the accumulation of CD8+ T cells with a terminally differentiated effector phenotype. Accordingly, BCAP-deficient CD8+ T cells have attenuated clonal expansion and altered effector and memory T cell development following infection with Listeria monocytogenes. Thus, induction of BCAP serves as a positive feedback circuit to enhance PI3K signaling in activated CD8+ T cells, thereby acting as a molecular checkpoint regulating effector and memory T cell development.

scholarly journals Homeostasis-Stimulated Proliferation Drives Naive T Cells to Differentiate Directly into Memory T Cells

2000 ◽  
Vol 192 (4) ◽  
pp. 549-556 ◽  
Author(s):  
Bryan K. Cho ◽  
Varada P. Rao ◽  
Qing Ge ◽  
Herman N. Eisen ◽  
Jianzhu Chen
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
T Cell Differentiation ◽  
Target Cells ◽  
Central Feature ◽  
Memory Cd8 T Cells ◽  
Memory T Cell

The developmental requirements for immunological memory, a central feature of adaptive immune responses, is largely obscure. We show that as naive CD8 T cells undergo homeostasis-driven proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon γ faster upon restimulation. Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28. These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.

Lowering TCR expression on naive CD8 + T cells does not affect memory T‐cell differentiation

2010 ◽  
Vol 89 (2) ◽  
pp. 322-325 ◽  
Author(s):  
Julie Leignadier ◽  
Julie Rooney ◽  
Jean‐François Daudelin ◽  
Nathalie Labrecque
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Differentiation ◽  
Memory T Cell

scholarly journals 668 Lipid-instructed metabolic rewiring unleash the anti-tumor potential of CD8+ T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A696-A696
Author(s):  
Teresa Manzo ◽  
Carina Nava Lauveson ◽  
Teresa Maria Frasconi ◽  
Silvia Tiberti ◽  
Ignazio Caruana ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mitochondrial Function ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Metabolic Reprogramming ◽  
Tumor Control ◽  
Metabolic Fitness

BackgroundAdoptive cell therapy (ACT) harnesses the immune system to recognise tumor cells and carry out an anti-tumor function. However, metabolic constraints imposed by the tumour microenvironment (TME) suppress anti-tumor responses of CTL by reshaping their metabolism and epigenetic landscape. We have recently demonstrated that progressive accumulation of specific long-chain fatty acids (LCFAs) impair mitochondrial function and drives CD8+ T cell dysfunction. In this scenario, maintaining T cells in a less-differentiated state and with high metabolic plasticity during ex vivo T cell production and after infusion may have a strong therapeutic impact. Here, we propose a novel strategy to boost ACT efficacy by implementing T cell long-term functionality, metabolic fitness and preventing exhaustion through lipid-induced mitochondrial rewiring.MethodsWe screen different LCFAs and assess their ability to shape CD8+ T cell differentiation using multi-parametric flow cytometry, proliferation and cytotoxic assays, together with a complete transcriptomic and epigenomic profiling. Metabolic reprogramming of lipid-treated CD8+ T cell was examined by bioenergetic flux measurements paired with metabolomic and lipidomic analysis. Finally, the anti-tumor responses of lipid-instructed CD8 T cells was evaluated in a melanoma mouse model, known to poorly respond to immunotherapy.ResultsLCFAs-treated CD8+ T cells are endowed with highly effector and cytotoxic features but still retaining a memory-like phenotype with decreased PD1 protein levels. Consistently, analysis of the bioenergetic profile and mitochondrial activity has shown that LCFA-instructed CD8+ T cells display a greater mitochondrial fitness. Thus, in vitro LCFA-instructed CD8+ T cells are characterized by higher mitochondrial fitness, potent functionality, memory-like phenotype and PD-1 down-regulation, overall evoking the ideal T cell population associated with a productive anti-tumor response. The therapeutic potential of CD8 T cells lipid-induced metabolic rewiring was further confirmed in vivo. ACT performed with LCFA-reprogrammed CD8 T cells induces higher frequency of memory T cells, which show high polyfunctionality and mitochondrial function, decreased PD1 expression, ultimately resulting in improved tumor control. In addition, LCFA-induced metabolic rewiring during manufacturing of human CAR-redirected T cells, generated a CD8+ T cell memory-like population with higher mitochondrial fitness coupled with a much potent cytotoxic activity.ConclusionsThese results suggest that LCFAs dictate the fate of CD8+ T cell differentiation and could be considered as a molecular switch to fine-tune memory T cell formation and metabolic fitness maintenance, linking lipid metabolism to anti-tumor surveillance. This will be of fundamental importance for a new generation of adoptive T cell-based therapies.Ethics ApprovalThe experiments described were performed in accordance with the European Union Guideline on Animal Experiments and mouse protocols were approved by Italian Ministry of Health and the IEO Committee.

scholarly journals Role of PD-1 during effector CD8 T cell differentiation

2018 ◽  
Vol 115 (18) ◽  
pp. 4749-4754 ◽  
Author(s):  
Eunseon Ahn ◽  
Koichi Araki ◽  
Masao Hashimoto ◽  
Weiyan Li ◽  
James L. Riley ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Lcmv Infection

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti–PD-L1 or anti–PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

scholarly journals Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection

2021 ◽  
Vol 218 (8) ◽  
Author(s):  
J. Justin Milner ◽  
Clara Toma ◽  
Sara Quon ◽  
Kyla Omilusik ◽  
Nicole E. Scharping ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Small Molecule ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Cell Phenotype ◽  
Effector T Cell ◽  
Terminal Effector

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector–specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule–mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.

scholarly journals Extracellular signal-regulated kinase (ERK) pathway control of CD8+ T cell differentiation

2020 ◽  
Author(s):  
Marcos P Damasio ◽  
Julia M Marchingo ◽  
Laura Spinelli ◽  
Jens Hukelmann ◽  
Doreen Cantrell ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Antigen Receptor ◽  
T Cell Differentiation ◽  
Signalling Pathways ◽  
Extracellular Signal

The integration of multiple signalling pathways that co-ordinate T cell metabolism and transcriptional reprogramming is required to drive T cell differentiation and proliferation. One key T cell signalling module is mediated by extracellular signal-regulated kinases (ERKs) which are activated in response to antigen receptor engagement. The activity of ERKs is often used to report antigen receptor occupancy but the full details of how ERKs control T cell activation is not understood. Accordingly, we have used mass spectrometry to explore how ERK signalling pathways control antigen receptor driven proteome restructuring in CD8+ T cells to gain insights about the biological processes controlled by ERKs in primary lymphocytes. Quantitative analysis of &gt;8000 proteins identified 900 ERK regulated proteins in activated CD8+ T cells. The data identify both positive and negative regulatory roles for ERKs during T cell activation and reveal that ERK signalling primarily controls the repertoire of transcription factors, cytokines and cytokine receptors expressed by activated T cells. It was striking that a large proportion of the proteome restructuring that is driven by triggering of the T cell antigen receptor is not dependent on ERK activation. However, the selective targets of the ERK signalling module include the critical effector molecules and the cytokines that allow T cell communication with other immune cells to mediate adaptive immune responses.

Sign in / Sign up

Export Citation Format

Share Document