Decreases in Percentages of Naïve CD4 and CD8 T Cells and Increases in Percentages of Memory CD8 T-Cell Subsets in the Peripheral Blood Lymphocyte Populations of A-Bomb Survivors

Abstract Antigen-driven activation of CD8+ T cells results in the development of a robust anti-pathogen response and ultimately leads to the establishment of long-lived memory T cells. During the primary response, CD8+ T cells interact multiple times with cognate antigen on distinct types of antigen-presenting cells. The timing, location and context of these antigen encounters significantly impact the differentiation programs initiated in the cells. Moderate re-activation in the periphery promotes the establishment of the tissue-resident memory T cells that serve as sentinels at the portal of pathogen entry. Under some circumstances, moderate re-activation of T cells in the periphery can result in the excessive expansion and accumulation of circulatory memory T cells, a process called memory inflation. In contrast, excessive re-activation stimuli generally impede conventional T-cell differentiation programs and can result in T-cell exhaustion. However, these conditions can also elicit a small population of exhausted T cells with a memory-like signature and self-renewal capability that are capable of responding to immunotherapy, and restoration of functional activity. Although it is clear that antigen re-encounter during the primary immune response has a significant impact on memory T-cell development, we still do not understand the molecular details that drive these fate decisions. Here, we review our understanding of how antigen encounters and re-activation events impact the array of memory CD8+ T-cell subsets subsequently generated. Identification of the molecular programs that drive memory T-cell generation will advance the development of new vaccine strategies that elicit high-quality CD8+ T-cell memory.

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The lncRNA Snhg1-Vps13D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00492-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Yanyan Zhang ◽

Baohua Li ◽

Qiang Bai ◽

Pengcheng Wang ◽

Gang Wei ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Expression Pattern ◽

Cd8 T Cells ◽

Vesicle Trafficking ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Memory Cd8 T Cells ◽

Memory Cd8 T Cell

AbstractThe efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naivehi-effectorlo-memoryhi expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.

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Influenza- and MCMV-induced memory CD8 T cells control respiratory vaccinia virus infection despite residence in distinct anatomical niches

Mucosal Immunology ◽

10.1038/s41385-020-00373-4 ◽

2021 ◽

Author(s):

Suzanne P. M. Welten ◽

Josua Oderbolz ◽

Vural Yilmaz ◽

Susanna R. Bidgood ◽

Victoria Gould ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vaccinia Virus ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Protective Capacity ◽

Peripheral Tissues ◽

Memory Cd8 T Cells ◽

Memory Cd8 T Cell

AbstractInduction of memory CD8 T cells residing in peripheral tissues is of interest for T cell-based vaccines as these cells are located at mucosal and barrier sites and can immediately exert effector functions, thus providing protection in case of local pathogen encounter. Different memory CD8 T cell subsets patrol peripheral tissues, but it is unclear which subset is superior in providing protection upon secondary infections. We used influenza virus to induce predominantly tissue resident memory T cells or cytomegalovirus to elicit a large pool of effector-like memory cells in the lungs and determined their early protective capacity and mechanism of reactivation. Both memory CD8 T cell pools have unique characteristics with respect to their phenotype, localization, and maintenance. However, these distinct features do not translate into different capacities to control a respiratory vaccinia virus challenge in an antigen-specific manner, although differential activation mechanisms are utilized. While influenza-induced memory CD8 T cells respond to antigen by local proliferation, MCMV-induced memory CD8 T cells relocate from the vasculature into the tissue in an antigen-independent and partially chemokine-driven manner. Together these results bear relevance for the development of vaccines aimed at eliciting a protective memory CD8 T cell pool at mucosal sites.

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Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

Cellular Physiology and Biochemistry ◽

10.1159/000491532 ◽

2018 ◽

Vol 47 (6) ◽

pp. 2187-2198 ◽

Cited By ~ 9

Author(s):

Zhen Zhang ◽

Chaoqi Zhang ◽

Feng Li ◽

Bin Zhang ◽

Yi Zhang

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Adoptive T Cell Therapy ◽

T Cell Subsets ◽

Immune Checkpoints ◽

Signal Pathways ◽

Cell Based Therapy ◽

Memory Cd8 T Cell

MicroRNAs (miRNAs) have emerged as crucial regulators of T lymphocyte survival, differentiation and function, all of which are key factors impacting the outcome of adoptive T cell-based immunotherapy. It has become increasingly clear that the adoptive transfer of memory CD8+ T cell subsets is highly correlated with objective clinical responses for patients with advanced cancer. However, it is unclear how to improve the long-term persistence of transferred CD8+ T cells using miRNAs. Here, we highlight the current advances in our understanding of the role of miRNAs in regulating the differentiation of memory CD8+ T cells. We specifically discuss the effect of miRNAs on key transcription factors, immune checkpoints and signal pathways, which contribute to the differentiation of effector and memory T cell subsets. Ultimately, miRNAs may be easily integrated into existing T cell receptor (TCR) and chimeric antigen receptor (CAR) platforms to promote adoptive T cell therapy with multiple advantages. Thus, combining T cell-based therapy with miRNAs could be considered a promising and robust strategy for cancer treatment.

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Faculty Opinions recommendation of Identical beta cell-specific CD8(+) T cell clonotypes typically reside in both peripheral blood lymphocyte and pancreatic islets.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1063892.519132 ◽

2007 ◽

Author(s):

Mark Atkinson

Keyword(s):

T Cell ◽

Beta Cell ◽

Pancreatic Islets ◽

Peripheral Blood Lymphocyte ◽

Peripheral Blood ◽

Blood Lymphocyte ◽

Cd8 T Cell

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Mitochondrial Dysfunction Associates With Acute T Lymphocytopenia and Impaired Functionality in COVID-19 Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.799896 ◽

2022 ◽

Vol 12 ◽

Author(s):

Yufei Mo ◽

Kelvin Kai-Wang To ◽

Runhong Zhou ◽

Li Liu ◽

Tianyu Cao ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mitochondrial Dysfunction ◽

Cd8 T Cells ◽

Functional Impairment ◽

Cell Loss ◽

Cd8 T Cell ◽

Underlying Mechanism ◽

T Cell Subsets ◽

Effector Memory

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.

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TLR3 essentially promotes protective class I–restricted memory CD8+ T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients

Blood ◽

10.1182/blood-2011-06-362582 ◽

2012 ◽

Vol 119 (4) ◽

pp. 967-977 ◽

Cited By ~ 79

Author(s):

Agostinho Carvalho ◽

Antonella De Luca ◽

Silvia Bozza ◽

Cristina Cunha ◽

Carmen D'Angelo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Aspergillus Fumigatus ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Class I ◽

Class I Mhc ◽

Cell Responses ◽

Memory Cd8 T Cell

Abstract Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8+ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8+ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4+ and CD8+ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8+ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8+ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8+ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients.

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Cortisol and epinephrine control opposing circadian rhythms in T cell subsets

Blood ◽

10.1182/blood-2008-11-190769 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5134-5143 ◽

Cited By ~ 172

Author(s):

Stoyan Dimitrov ◽

Christian Benedict ◽

Dennis Heutling ◽

Jürgen Westermann ◽

Jan Born ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Circadian Rhythms ◽

Cd8 T Cells ◽

Low Dose ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Counts

Abstract Pronounced circadian rhythms in numbers of circulating T cells reflect a systemic control of adaptive immunity whose mechanisms are obscure. Here, we show that circadian variations in T cell subpopulations in human blood are differentially regulated via release of cortisol and catecholamines. Within the CD4+ and CD8+ T cell subsets, naive cells show pronounced circadian rhythms with a daytime nadir, whereas (terminally differentiated) effector CD8+ T cell counts peak during daytime. Naive T cells were negatively correlated with cortisol rhythms, decreased after low-dose cortisol infusion, and showed highest expression of CXCR4, which was up-regulated by cortisol. Effector CD8+ T cells were positively correlated with epinephrine rhythms, increased after low-dose epinephrine infusion, and showed highest expression of β-adrenergic and fractalkine receptors (CX3CR1). Daytime increases in cortisol via CXCR4 probably act to redistribute naive T cells to bone marrow, whereas daytime increases in catecholamines via β-adrenoceptors and, possibly, a suppression of fractalkine signaling promote mobilization of effector CD8+ T cells from the marginal pool. Thus, activation of the major stress hormones during daytime favor immediate effector defense but diminish capabilities for initiating adaptive immune responses.

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TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis

Journal of Experimental Medicine ◽

10.1084/jem.20181778 ◽

2019 ◽

Vol 216 (7) ◽

pp. 1682-1699 ◽

Cited By ~ 19

Author(s):

Lisa A. Mielke ◽

Yang Liao ◽

Ella Bridie Clemens ◽

Matthew A. Firth ◽

Brigette Duckworth ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Fate ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Double Positive ◽

Cell Fate Decisions ◽

Healthy Humans ◽

Tc17 Cells

Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8+ T cell subsets. IL-17–producing CD8+ T cells isolated from healthy humans were also distinct from CD8+IL-17− T cells and enriched in pathways driven by MAF and RORγt. Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.

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