p21CIP1/WAF1 Controls Proliferation of Activated/Memory T Cells and Affects Homeostasis and Memory T Cell Responses

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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Peripheral and lung resident memory T cell responses against SARS-CoV-2

Nature Communications ◽

10.1038/s41467-021-23333-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Judith Grau-Expósito ◽

Nerea Sánchez-Gaona ◽

Núria Massana ◽

Marina Suppi ◽

Antonio Astorga-Gamaza ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Acute Infection ◽

T Cell Responses ◽

Lung Parenchyma ◽

Viral Proteins ◽

Memory T Cell ◽

Cell Responses ◽

Resident Memory T Cells

AbstractResident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.

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Dietary Regulation of Memory T Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21124363 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4363 ◽

Cited By ~ 1

Author(s):

Nicholas Collins

Keyword(s):

T Cells ◽

T Cell ◽

Cell Function ◽

Memory T Cells ◽

T Cell Responses ◽

Memory T Cell ◽

Cell Responses ◽

Vaccination Strategies ◽

T Cell Function ◽

Cancer Immunotherapies

Memory T cells are a fundamental component of immunological memory, providing rapid and potent host protection against secondary challenges. As such, memory T cells are key targets in the design of vaccination strategies and cancer immunotherapies, making it critical to understand the factors and mechanisms that regulate their biology. Diet is an environmental feature that impacts virtually all aspects of host physiology. However, the influence of specific dietary regiments and nutritional components on the immune system is only just starting to be uncovered. This article will review literature regarding the impact of diet and nutrition on memory T cell development, maintenance and function. It was recently shown that caloric restriction without undernutrition enhances memory T cell function, while diets high in fiber are also beneficial. However, memory T cell responses are dysfunctional in extreme nutritional states, such as undernutrition and diet-induced obesity. Therefore, diet and host nutritional status are major regulators of memory T cell biology and host fitness. To define the dietary balance required to promote optimal memory T cell responses could allow for the implementation of rational diet-based therapies that prevent or treat disease. Furthermore, that certain dietary regiments can enhance memory T cell function indicates the possibility of harnessing the underlying mechanisms in the design of novel vaccination strategies and cancer immunotherapies.

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Variances in Antiviral Memory T-Cell Repertoire of CD45RA- and CD62L-Depleted Lymphocyte Products Reflect the Need of Individual T-Cell Selection Strategies to Reduce the Risk of GvHD while Preserving Antiviral Immunity in Adoptive T-Cell Therapy

Transfusion Medicine and Hemotherapy ◽

10.1159/000516284 ◽

2021 ◽

pp. 1-14

Author(s):

Caroline Mangare ◽

Sabine Tischer-Zimmermann ◽

Agnes Bonifacius ◽

Sebastian B. Riese ◽

Anna Christina Dragon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Cell Activity ◽

T Cell Responses ◽

Adoptive T Cell Therapy ◽

Effector Memory ◽

Hematopoietic Stem ◽

Memory T Cell ◽

Cell Responses

Introduction: Viral infections and reactivations still remain a cause of morbidity and mortality after hematopoietic stem cell transplantation due to immunodeficiency and immunosuppression. Transfer of unmanipulated donor-derived lymphocytes (DLI) represents a promising strategy for improving cellular immunity but carries the risk of graft versus host disease (GvHD). Depleting alloreactive naïve T cells (TN) from DLIs was implemented to reduce the risk of GvHD induction while preserving antiviral memory T-cell activity. Here, we compared two TN depletion strategies via CD45RA and CD62L expression and investigated the presence of antiviral memory T cells against human adenovirus (AdV) and Epstein-Barr virus (EBV) in the depleted fractions in relation to their functional and immunophenotypic characteristics. Methods: T-cell responses against ppEBV_EBNA1, ppEBV_Consensus and ppAdV_Hexon within TN-depleted (CD45RA−/CD62L−) and TN-enriched (CD45RA+/CD62L+) fractions were quantified by interferon-gamma (IFN-γ) ELISpot assay after short- and long-term in vitro stimulation. T-cell frequencies and immunophenotypic composition were assessed in all fractions by flow cytometry. Moreover, alloimmune T-cell responses were evaluated by mixed lymphocyte reaction. Results: According to differences in the phenotype composition, antigen-specific T-cell responses in CD45RA− fraction were up to 2 times higher than those in the CD62L− fraction, with the highest increase (up to 4-fold) observed after 7 days for ppEBV_EBNA1-specific T cells. The CD4+ effector memory T cells (TEM) were mainly responsible for EBV_EBNA1- and AdV_Hexon-specific T-cell responses, whereas the main functionally active T cells against ppEBV_Consensus were CD8+ central memory T cells (TCM) and TEM. Moreover, comparison of both depletion strategies indicated that alloreactivity in CD45RA− was lower than that in CD62L− fraction. Conclusion: Taken together, our results indicate that CD45RA depletion is a more suitable strategy for generating TN-depleted products consisting of memory T cells against ppEBV_EBNA1 and ppAdV_Hexon than CD62L in terms of depletion effectiveness, T-cell functionality and alloreactivity. To maximally exploit the beneficial effects mediated by antiviral memory T cells in TN-depleted products, depletion methods should be selected individually according to phenotype composition and CD4/CD8 antigen restriction. TN-depleted DLIs may improve the clinical outcome in terms of infections, GvHD, and disease relapse if selection of pathogen-specific donor T cells is not available.

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Comparison of the Development of SARS-Coronavirus-2-Specific Cellular Immunity, and Central Memory CD4+ T-Cell Responses Following Infection versus Vaccination

Vaccines ◽

10.3390/vaccines9121439 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1439

Author(s):

Kevin M. Dennehy ◽

Eva Löll ◽

Christine Dhillon ◽

Johanna-Maria Classen ◽

Tobias D. Warm ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Responses ◽

Central Memory ◽

Cd4 T Cell ◽

Memory T Cell ◽

Cell Responses ◽

Specific Effector ◽

Memory Cd4 T Cells

Memory T-cell responses following infection with coronaviruses are reportedly long-lived and provide long-term protection against severe disease. Whether vaccination induces similar long-lived responses is not yet clear since, to date, there are limited data comparing memory CD4+ T-cell responses induced after SARS-CoV-2 infection versus following vaccination with BioNTech/Pfizer BNT162b2. We compared T-cell immune responses over time after infection or vaccination using ELISpot, and memory CD4+ T-cell responses three months after infection/vaccination using activation-induced marker flow cytometric assays. Levels of cytokine-producing T-cells were remarkably stable between three and twelve months after infection, and were comparable to IFNγ+ and IFNγ+IL-2+ T-cell responses but lower than IL-2+ T-cell responses at three months after vaccination. Consistent with this finding, vaccination and infection elicited comparable levels of SARS-CoV-2 specific CD4+ T-cells after three months in addition to comparable proportions of specific central memory CD4+ T-cells. By contrast, the proportions of specific effector memory CD4+ T-cells were significantly lower, whereas specific effector CD4+ T-cells were higher after infection than after vaccination. Our results suggest that T-cell responses—as measured by cytokine expression—and the frequencies of SARS-CoV-2-specific central memory CD4+T-cells—indicative of the formation of the long-lived memory T-cell compartment—are comparably induced after infection and vaccination.

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Persistent Cellular Immunity to SARS-CoV-2 Infection

10.1101/2020.12.08.416636 ◽

2020 ◽

Author(s):

Gaëlle Breton ◽

Pilar Mendoza ◽

Thomas Hagglof ◽

Thiago Y. Oliveira ◽

Dennis Schaefer-Babajew ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cell Division ◽

T Cell ◽

T Cell Responses ◽

Memory T Cell ◽

Cell Responses ◽

Paired Samples ◽

Specific Memory ◽

Immune Alterations

AbstractSARS-CoV-2 is responsible for an ongoing pandemic that affected millions of individuals around the globe. To gain further understanding of the immune response in recovered individuals we measured T cell responses in paired samples obtained an average of 1.3 and 6.1 months after infection from 41 individuals. The data indicate that recovered individuals show persistent polyfunctional SARS-CoV-2 antigen specific memory that could contribute to rapid recall responses. In addition, recovered individuals show enduring immune alterations in relative numbers of CD4+ and CD8+ T cells, expression of activation/exhaustion markers, and cell division.SummaryWe show that SARS-CoV-2 infection elicits broadly reactive and highly functional memory T cell responses that persist 6 months after infection. In addition, recovered individuals show enduring immune alterations in CD4+ and CD8+ T cells compartments.

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Baseline Levels of Influenza-Specific CD4 Memory T-Cells Affect T-Cell Responses to Influenza Vaccines

PLoS ONE ◽

10.1371/journal.pone.0002574 ◽

2008 ◽

Vol 3 (7) ◽

pp. e2574 ◽

Cited By ~ 38

Author(s):

Xiao-Song He ◽

Tyson H. Holmes ◽

Sanae Sasaki ◽

Maria C. Jaimes ◽

George W. Kemble ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

T Cell Responses ◽

Influenza Vaccines ◽

Cell Responses ◽

Baseline Levels

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Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen.

Journal of Experimental Medicine ◽

10.1084/jem.181.5.1935 ◽

1995 ◽

Vol 181 (5) ◽

pp. 1935-1940 ◽

Cited By ~ 205

Author(s):

L F Santamaria Babi ◽

L J Picker ◽

M T Perez Soler ◽

K Drzimalla ◽

P Flohr ◽

...

Keyword(s):

T Cells ◽

Atopic Dermatitis ◽

T Cell ◽

Contact Dermatitis ◽

Allergic Contact Dermatitis ◽

Memory T Cells ◽

Homing Receptor ◽

Memory T Cell ◽

Cell Responses ◽

Allergic Contact

The cutaneous lymphocyte-associated antigen (CLA) is the major T cell ligand for the vascular adhesion molecule E-selectin, and it has been proposed to be involved in the selective targeting of memory T cells reactive with skin-associated Ag to cutaneous inflammatory sites. To further investigate the relation of CLA and cutaneous T cell responses, we analyzed the CLA phenotype of circulating memory T cells in patients with allergic contact dermatitis and atopic dermatitis (AD) alone vs in patients manifesting bronchopulmonary atopy (asthma with or without AD) and nonallergic individuals. Significant T cell proliferative responses to Ni, a contact allergen, and to the house dust mite (HDM), an allergen to which sensitization is often observed in AD and/or asthma, was noted only in allergic and atopic individuals, respectively. When the minor circulating CLA+CD3+CD45RO+ subset was separated from the major CLA-CD3+CD45RO+ subpopulation in Ni-sensitive subjects, the Ni-dependent memory T cell response was largely confined to the CLA+ subset. A similar restriction of the T cell proliferative response to the CLA+ memory subset was observed for HDM in patients with AD alone. In HDM-sensitive patients with asthma with or without AD, however, the CLA- subset exhibited a strong antigen-dependent proliferation, in contrast to patients with AD alone, whose CLA- subset proliferated very weakly to HDM. In asthma with or without AD, the HDM-dependent proliferation slightly predominated in the CLA- when compared to the CLA+ subset. The functional linkage between CLA expression and disease-associated T cell effector function in AD was also demonstrated by the finding that the circulating CLA+ T cell subset in AD patients, but not nonatopic controls, selectively showed both evidence of prior activation (human histocompatibility antigen-DR expression) and spontaneous production of interleukin 4 but not interferon-gamma. Taken together, these observations demonstrate the correlation of CLA expression on circulating memory T cells and disease-associated memory T cell responses in cutaneous hypersensitivity, and they suggest the existence of mechanisms capable of sorting particular T cell Ag specificities and lymphokine patterns into homing receptor-defined memory subsets.

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Peripheral and lung resident T cell responses against SARS-CoV-2

10.21203/rs.3.rs-198819/v1 ◽

2021 ◽

Author(s):

Judith Grau-Expósito ◽

Nerea Sánchez-Gaona ◽

Núria Massana ◽

Marina Suppi ◽

Antonio Astorga-Gamaza ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

T Cell Responses ◽

Lung Parenchyma ◽

Viral Proteins ◽

Viral Spread ◽

Cell Responses ◽

Circulating Lymphocytes ◽

Resident Memory T Cells

Abstract Considering that SARS-CoV-2 interacts with the host at the respiratory tract mucosal interface, T cells strategically placed within these surfaces, namely resident memory T cells, will be essential to limit viral spread and disease. Importantly, these cells are mostly non-recirculating, which reduces the window of opportunity to examine circulating lymphocytes in blood as they home to the lung parenchyma. Here, we demonstrate that viral specific T cells can migrate and establish in the lung as resident memory T cells remaining detectable up to 10 months after initial infection. Moreover, focusing on the acute phase of the infection, we identified virus-specific T cell responses in blood with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Our study highlights IL-10 secretion by virus-specific T cells associated to a better outcome and the persistence of resident memory T cells as key players for future protection against SARS-CoV-2 infection.

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