Tuning T cell activation threshold and effector function with cross-reactive peptide ligands

We investigated whether human resting T cells could be activated to proliferate and display effector function in the absence of T cell receptor occupancy. We report that combination of interleukin 2 (IL-2), tumor necrosis factor alpha, and IL-6 activated highly purified naive (CD45RA+) and memory (CD45RO+) resting CD4+ T cells to proliferate. Under this condition, memory resting T cells could also display effector function as measured by lymphokine synthesis and help for immunoglobulin production by B cells. This novel Ag-independent pathway of T cell activation may play an important role in vivo in recruiting effector T cells at the site of immune response and in maintaining the clonal size of memory T cells in the absence of antigenic stimulation. Moreover, cytokines can induce proliferation of naive T cells without switch to memory phenotype and this may help the maintenance of the peripheral pool of naive T cells.

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Induction of polyclonal CD8+ T cell activation and effector function by Pertussis toxin

Cellular Immunology ◽

10.1016/j.cellimm.2010.11.003 ◽

2011 ◽

Vol 267 (1) ◽

pp. 50-55 ◽

Cited By ~ 7

Author(s):

Cathi Murphey ◽

Steve Chang ◽

Xue Zhang ◽

Bernard Arulanandam ◽

Thomas G. Forsthuber

Keyword(s):

T Cell ◽

T Cell Activation ◽

Pertussis Toxin ◽

Cell Activation ◽

Cd8 T Cell ◽

Effector Function

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In Vivo CD86 Blockade Inhibits CD4+ T Cell Activation, Whereas CD80 Blockade Potentiates CD8+ T Cell Activation and CTL Effector Function

The Journal of Immunology ◽

10.4049/jimmunol.168.8.3786 ◽

2002 ◽

Vol 168 (8) ◽

pp. 3786-3792 ◽

Cited By ~ 53

Author(s):

Thomas J. Lang ◽

Phuong Nguyen ◽

Robert Peach ◽

William C. Gause ◽

Charles S. Via

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Effector Function ◽

Cd4 T Cell

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Optical Control of CD8+ T Cell Metabolism and Effector Functions

Frontiers in Immunology ◽

10.3389/fimmu.2021.666231 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrea M. Amitrano ◽

Brandon J. Berry ◽

Kihong Lim ◽

Kyun-Do Kim ◽

Richard E. Waugh ◽

...

Keyword(s):

T Cells ◽

Cell Migration ◽

Membrane Potential ◽

T Cell ◽

T Cell Activation ◽

Mitochondrial Membrane ◽

Cell Activation ◽

Cell Metabolism ◽

Effector Function ◽

T Cell Migration

Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed “OptoMito-On” successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.

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Dynamics of T cell activation threshold tuning

Journal of Theoretical Biology ◽

10.1016/j.jtbi.2004.02.002 ◽

2004 ◽

Vol 228 (3) ◽

pp. 397-416 ◽

Cited By ~ 30

Author(s):

Hugo A. van den Berg ◽

David A. Rand

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Activation Threshold ◽

Threshold Tuning

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Critical Role for Cd8 in T Cell Receptor Binding and Activation by Peptide/Major Histocompatibility Complex Multimers

Journal of Experimental Medicine ◽

10.1084/jem.191.2.335 ◽

2000 ◽

Vol 191 (2) ◽

pp. 335-346 ◽

Cited By ~ 201

Author(s):

Mark A. Daniels ◽

Stephen C. Jameson

Keyword(s):

T Cell ◽

T Cell Receptor ◽

T Cell Activation ◽

Cell Activation ◽

Current Model ◽

Critical Role ◽

Cell Receptor ◽

Peptide Ligands ◽

Direct Role ◽

Class I Mhc

Recent data using MHC/peptide tetramers and dimers suggests that the T cell coreceptors, CD4 and CD8, although important for T cell activation, do not play a direct role in facilitating T cell receptor (TCR) binding to multivalent MHC/peptide ligands. Instead, a current model proposes that coreceptors are recruited only after a stable TCR–MHC/peptide complex has already formed and signaled. In contrast, we show using multimeric class I MHC/peptide ligands that CD8 plays a critical (in some cases obligatory) role in antigen-specific TCR binding. T cell activation, measured by calcium mobilization, was induced by multimeric but not monomeric ligands and also showed CD8 dependency. Our analysis using anti-CD8 antibodies revealed that binding to different epitopes of CD8 can either block or augment TCR–MHC/peptide interaction. These effects on TCR binding to high-affinity agonist ligands were even more pronounced when binding to multimeric low-affinity ligands, including TCR antagonists, was studied. Our data have important implications for the role of CD8 in TCR binding to MHC/peptide ligands and in T cell activation. In addition, our results argue against the view that multimeric MHC/peptide ligands bind directly and solely to the TCR; rather, our data highlight a pivotal contribution of CD8 for this association.

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Abstract 104: Deletion Of Myd88 In T-Cells Worsens Pathology In A Mouse Model Of Non-Ischemic Heart Failure Through Enhanced T-Cell Survival And Effector Function:

Circulation Research ◽

10.1161/res.129.suppl_1.104 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Abraham L Bayer ◽

Njabulo Ngwenyama ◽

Sasha Smolgovsky ◽

Ana Hernández Martínez ◽

Kuljeet Kaur ◽

...

Keyword(s):

Heart Failure ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Adaptor Protein ◽

Primary Response ◽

Effector Function ◽

Th1 Cells ◽

Adhesion Ability

Background: Heart failure (HF) is a leading cause of death worldwide, associated with cardiac and systemic inflammation. However, no anti-inflammatory therapies have shown success thus far. Damage associated molecular patterns (DAMPs) released in the heart can activate myeloid cells to promote antigen presentation to T-cells, which infiltrate the heart and participate in adverse cardiac remodeling. DAMP signaling converges onto the adaptor protein “Myeloid differentiation primary response 88” (MyD88). DAMP receptors and MyD88 are also expressed in T-cells, but their role in T-cell activation is unclear, and is unknown in the context of HF. We hypothesized that T-cell recognition of DAMPs through MyD88 causes “bystander activation” of T-cells and contributes to cardiac pathology in HF. Methods and Results: We reconstituted Tcra -/- mice, normally protected from HF, with WT or Myd88 -/- Type 1 helper T-cells (Th1) in the onset of transaortic constriction (TAC), a well-established model of HF. Surprisingly, we found that mice given Myd88 -/- Th1 cells exhibited significantly higher levels of cardiac T-cell infiltration, more severe fibrosis, and lower fractional shortening than mice given WT Th1 cells. We found that WT and Myd88 -/- Th1 cells had similar levels of IFNγ and Tbx21 by intracellular staining and RT-qPCR, indicating that MyD88 does not alter Th1 differentiation. However, Myd88 -/- Th1 cells secreted higher levels of IL-2 and TNFα, suggesting enhanced proliferative and pro-inflammatory effector function. We performed viability studies using live cell microscopy and measuring propidium iodide incorporation in real time, as well as by flow cytometry, and found that Myd88 -/- Th1 cells have a survival advantage compared to WT Th1 cells. Moreover, we found that Myd88 -/- Th1 cells exhibited higher levels of adhesion to ICAM-1 and VCAM-1, protein ligands involved in T-cell recruitment, compared to WT Th1 cells when perfused under conditions of shear flow. Conclusion: Together, these data demonstrate that T-cell MyD88 limits T-cell mediated pathology in HF by modulating Th1 effector function, survival, and adhesion ability. We identify novel role for T-cell MyD88 in cardiac inflammation that may be modulated in HF.

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