scholarly journals T cell-intrinsic vitamin A metabolism and its signaling are targets for memory T cell-based cancer immunotherapy

2021 ◽  
Author(s):  
Fumihiro Fujiki ◽  
Soyoko Morimoto ◽  
Akiko Katsuhara ◽  
Akane Okuda ◽  
Saeka Ogawa ◽  
...  
Keyword(s):  
T Cells ◽  
Retinoic Acid ◽  
Cell Differentiation ◽  
T Cell ◽  
Vitamin A ◽  
Cancer Immunotherapy ◽  
Memory T Cells ◽  
T Cell Differentiation ◽  
Vitamin A Metabolism ◽  
Memory T Cell

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh10 deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.

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 Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans

2005 ◽  
Vol 102 (22) ◽  
pp. 7916-7921 ◽  
Author(s):  
K. Song ◽  
R. L. Rabin ◽  
B. J. Hill ◽  
S. C. De Rosa ◽  
S. P. Perfetto ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Memory T Cells ◽  
T Cell Differentiation

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.

scholarly journals PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Roberto Tinoco ◽  
Emily N. Neubert ◽  
Christopher J. Stairiker ◽  
Monique L. Henriquez ◽  
Linda M. Bradley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Memory T Cells ◽  
Effector T Cells ◽  
T Cell Differentiation ◽  
Virus Infections ◽  
Effector T Cell ◽  
Memory T Cell ◽  
Cell Responses

Effective T cell differentiation during acute virus infections leads to the generation of effector T cells that mediate viral clearance, as well as memory T cells that confer protection against subsequent reinfection. While inhibitory immune checkpoints have been shown to promote T cell dysfunction during chronic virus infections and in tumors, their roles in fine tuning the differentiation and responses of effector and memory T cells are only just beginning to be appreciated. We previously identified PSGL-1 as a fundamental regulator of T cell exhaustion that sustains expression of several inhibitory receptors, including PD-1. We now show that PSGL-1 can restrict the magnitude of effector T cell responses and memory T cell development to acute LCMV virus infection by limiting survival, sustaining PD-1 expression, and reducing effector responses. After infection, PSGL-1-deficient effector T cells accumulated to a greater extent than wild type T cells, and preferentially generated memory precursor cells that displayed enhanced accumulation and functional capacity in response to TCR stimulation as persisting memory cells. Although, PSGL-1-deficient memory cells did not exhibit inherent greater sensitivity to cell death, they failed to respond to a homologous virus challenge after adoptive transfer into naïve hosts indicating an impaired capacity to generate memory effector T cell responses in the context of viral infection. These studies underscore the function of PSGL-1 as a key negative regulator of effector and memory T cell differentiation and suggest that PSGL-1 may limit excessive stimulation of memory T cells during acute viral infection.

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 Detection of IFNγ-Secreting CD4+ and CD8+ Memory T Cells in COVID-19 Convalescents after Stimulation of Peripheral Blood Mononuclear Cells with Live SARS-CoV-2

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1490
Author(s):  
Victoria Matyushenko ◽  
Irina Isakova-Sivak ◽  
Igor Kudryavtsev ◽  
Arina Goshina ◽  
Anna Chistyakova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Natural Infection ◽  
Intracellular Cytokine Staining ◽  
T Cell Responses ◽  
Effector Memory ◽  
Memory T Cell ◽  
Cell Responses ◽  
Stimulation Of

Background: New coronavirus SARS-CoV-2, a causative agent of the COVID-19 pandemic, has been circulating among humans since November 2019. Multiple studies have assessed the qualitative and quantitative characteristics of virus-specific immunity in COVID-19 convalescents, however, some aspects of the development of memory T-cell responses after natural SARS-CoV-2 infection remain uncovered. Methods: In most of published studies T-cell immunity to the new coronavirus is assessed using peptides corresponding to SARS-CoV-1 or SARS-CoV-2 T-cell epitopes, or with peptide pools covering various parts of the viral proteins. Here, we determined the level of CD4+ and CD8+ memory T-cell responses in COVID-19 convalescents by stimulating PBMCs collected 1 to 6 months after recovery with sucrose gradient-purified live SARS-CoV-2. IFNγ production by the central and effector memory helper and cytotoxic T cells was assessed by intracellular cytokine staining assay and flow cytometry. Results: Stimulation of PBMCs with live SARS-CoV-2 revealed IFNγ-producing T-helper effector memory cells with CD4+CD45RA−CCR7− phenotype, which persisted in circulation for up to 6 month after COVID-19. In contrast, SARS-CoV-2-specific IFNγ-secreting cytotoxic effector memory T cells were found at significant levels only shortly after the disease, but rapidly decreased over time. Conclusion: The stimulation of immune cells with live SARS-CoV-2 revealed a rapid decline in the pool of effector memory CD8+, but not CD4+, T cells after recovery from COVID-19. These data provide additional information on the development and persistence of cellular immune responses after natural infection, and can inform further development of T cell-based SARS-CoV-2 vaccines.

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