scholarly journals Role of T cell receptor signaling in CD8 T cell memory

2015 ◽  
Author(s):  
◽  
Karin M. Knudson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Immunological Memory ◽  
Cell Receptor ◽  
T Cell Memory ◽  
Cell Memory ◽  
Memory Cd8 T Cells ◽  
Memory Differentiation

The generation of immunological memory is the basis for vaccination. The development of memory CD8 T cells is required for long-term protection against intracellular pathogens, such as viruses, and tumors. While the importance of memory generation has been recognized for over 30 years, the mechanism by which memory CD8 T cells arise during immune responses is still not fully understood. T cell receptor (TCR) interaction with antigen (immunogenic peptide)-bound MHC is necessary for activation and differentiation of CD8 T cells. Yet, how the resulting TCR signal regulates T cell memory is unknown. In this dissertation, we investigated the role that the TCR signal plays in memory differentiation. First, we explain how the strength of pMHC-TCR interaction affects memory generation. We also demonstrate that the signals for the development of memory are different depending on TCR ligand strength. Finally, we define a mechanism by which TCR signaling programs memory differentiation. All vaccines utilize pathogen-specific antigens to induce immunological memory. By understanding how antigenic signals program memory differentiation, it will be possible to specifically manipulate this process. We can then produce more effective and longer lasting memory cells.

scholarly journals Regulation of Memory CD8 T-Cell Differentiation by Cyclin-Dependent Kinase Inhibitor p27Kip1

2010 ◽  
Vol 30 (21) ◽  
pp. 5145-5159 ◽  
Author(s):  
Anju Singh ◽  
Anna Jatzek ◽  
Erin Hemmila Plisch ◽  
Rajini Srinivasan ◽  
John Svaren ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Kinase Inhibitor ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Cell Memory ◽  
Memory Cd8 T Cells ◽  
Cyclin Dependent Kinase Inhibitor

ABSTRACT Induction of potent T-cell memory is the goal of vaccinations, but the molecular mechanisms that regulate the formation of memory CD8 T cells are not well understood. Despite the recognition that controls of cellular proliferation and apoptosis govern the number of memory T cells, the cell cycle regulatory mechanisms that control these key cellular processes in CD8 T cells during an immune response are poorly defined. Here, we have identified the cyclin-dependent kinase inhibitor p27Kip1 as a critical regulator of the CD8 T-cell homeostasis at all phases of the T-cell response to an acute viral infection in mice. By acting as a timer for cell cycle exit, p27Kip1 curtailed the programmed expansion of interleukin-2-producing memory precursors and markedly limited the magnitude and quality of CD8 T-cell memory. In the absence of p27Kip1, CD8 T cells showed superior recall responses shortly after vaccination with recombinant Listeria monocytogenes. Additionally, we show that p27Kip1 constrains proliferative renewal of memory CD8 T cells, especially of the effector memory subset. These findings provide critical insights into the cell cycle regulation of CD8 T-cell homeostasis and suggest that modulation of p27Kip1 could bolster vaccine-induced T-cell memory and protective immunity.

scholarly journals Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Frank Penkava ◽  
Martin Del Castillo Velasco-Herrera ◽  
Matthew D. Young ◽  
Nicole Yager ◽  
Lilian N. Nwosu ◽  
...  
Keyword(s):  
T Cells ◽  
Psoriatic Arthritis ◽  
T Cell ◽  
Single Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Memory Cd8 T Cells ◽  
Immune Mediated ◽  
Cellular Immune

Abstract Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

scholarly journals T cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling

2021 ◽  
Author(s):  
Shu Shien Chin ◽  
Erik Guillen ◽  
Laurent Chorro ◽  
Sooraj Achar ◽  
Susanne Oberle ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Chromatin Accessibility ◽  
Functional Fitness ◽  
Memory Cd8 T Cells

Cognate antigen signal controls CD8+ T cell priming, expansion size and effector versus memory cell fates, but it is not known if and how it modulates the functional features of memory CD8+ T cells. Here we show that the strength of T cell receptor (TCR) signaling determines the requirement for interleukin-2 (IL-2) signals to form a pool of memory CD8+ T cells that competitively re-expand upon secondary antigen encounter. Combining strong TCR and intact IL-2 signaling synergistically induces genome-wide chromatin accessibility in regions targeting a wide breadth of biological processes, consistent with their greater functional fitness. Chromatin accessibility in promoters of genes encoding for stem cell, cell cycle and calcium-related proteins correlated with faster intracellular calcium accumulation, initiation of cell cycle and more robust expansion. High-dimensional flow-cytometry analysis also highlights higher subset diversity and phenotypes. These results formally establish that epitope selection in vaccine design strongly impacts memory CD8+ T cell epigenetic programming and functions.

scholarly journals Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

2008 ◽  
Vol 14 (12) ◽  
pp. 1390-1395 ◽  
Author(s):  
Angel Varela-Rohena ◽  
Peter E Molloy ◽  
Steven M Dunn ◽  
Yi Li ◽  
Megan M Suhoski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Hiv 1
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