scholarly journals 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

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

<b><i>Introduction:</i></b> 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 (T<sub>N</sub>) from DLIs was implemented to reduce the risk of GvHD induction while preserving antiviral memory T-cell activity. Here, we compared two T<sub>N</sub> 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. <b><i>Methods:</i></b> T-cell responses against ppEBV_EBNA1, ppEBV_Consensus and ppAdV_Hexon within T<sub>N</sub>-depleted (CD45RA<sup>−</sup>/CD62L<sup>−</sup>) and T<sub>N</sub>-enriched (CD45RA<sup>+</sup>/CD62L<sup>+</sup>) fractions were quantified by interferon-gamma (IFN-γ) ELISpot assay after short- and long-term <i>in vitro</i> 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. <b><i>Results:</i></b> According to differences in the phenotype composition, antigen-specific T-cell responses in CD45RA<sup>−</sup> fraction were up to 2 times higher than those in the CD62L<sup>−</sup> fraction, with the highest increase (up to 4-fold) observed after 7 days for ppEBV_EBNA1-specific T cells. The CD4<sup>+</sup> effector memory T cells (T<sub>EM</sub>) 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<sup>+</sup> central memory T cells (T<sub>CM</sub>) and T<sub>EM</sub>. Moreover, comparison of both depletion strategies indicated that alloreactivity in CD45RA<sup>−</sup> was lower than that in CD62L<sup>−</sup> fraction. <b><i>Conclusion:</i></b> Taken together, our results indicate that CD45RA depletion is a more suitable strategy for generating T<sub>N</sub>-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 T<sub>N</sub>-depleted products, depletion methods should be selected individually according to phenotype composition and CD4/CD8 antigen restriction. T<sub>N</sub>-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.

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.

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

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.

scholarly journals Dietary Regulation of Memory T Cells

2020 ◽  
Vol 21 (12) ◽  
pp. 4363 ◽  
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.

Allogeneic Memory T Cells Derived from Host DC-Activated CD44loCD8+ T Precursors Sustain Host Tissue Injury of Ongoing Graft-versus-Host Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3040-3040
Author(s):  
Yi Zhang ◽  
Gerard Joe ◽  
Elizabeth Hexner ◽  
Jiang Zhu ◽  
Stephen G. Emerson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Effector Memory ◽  
Memory Phenotype ◽  
Memory T Cell ◽  
Cell Responses ◽  
With Memory

Abstract Graft-versus-host disease (GVHD) directed against minor histocompatibility antigen (miHAs) evolves over weeks to months, suggesting a requirement for persistent alloreactive donor T cells. In patients with allogeneic bone marrow transplantation (allo-BMT), persistency of GVHD is accompanied with elevated allogeneic CD4+ T cells with memory phenotype in peripheral blood. In contrast, several other studies have recently shown that T cells with memory phenotype (CD44hiCD62Lhi/lo) from normal donor mice do not induce acute GVHD. While these T cells with memory phenotype may be induced by environmental antigenic stimulation or may represent cells undergoing homeostasis in vivo, we found that early activated donor CD44hiCD8+ T cells with effector/memory phenotype upon ex vivo host DC stimulation are also functional defective in GVHD induction in vivo. However, whether alloreactive memory T cells might develop in vivo in recipient with ongoing GVHD, and if this is the case, whether these in vivo generated alloreactive memory T cells may be responsbile for persistency of GVHD, remain unknown. Using the C3H.SW anti-C57BL/6 (B6) and B6 anti-BALB.B mouse models of human GVHD directed against miHAs, we found that alloreactive CD8+ T cells secreting high levels of IFN-γ in recipient mice receiving C3H.SW CD44loCD8+ T cells + T−BM peaked by day 14, declined by day 28, and increased again after 35 days of transplantation, corresponding to the kinetics of primary and memory T cell responses. Indeed, while donor C3H.SW CD8+ T cells recovered from these B6 mice receiving C3H.SW CD44loCD8+ T cells + T−BM 10 days after allo-BMT, at the peak time of primary allogeneic immune response, upregulated the expression of effector marker CD25, donor CD8+ T cells recovered 42 days after allo-BMT from B6 mice with ongoing GVHD, at the time of memory T cell development, expressed high levels of CD44 and CD122 but down-regulated CD25. However, both d10-CD8+ and d42-CD8+ T cells expressed identical levels of cytotoxic molecules including granzyme B, perforin and FasL and were able to kill B6 mouse-derived EL-4 leukemic cells. Compared to naïve CD44loCD8+ T cells that were lost after cultured in the presence of IL-2+IL-15 for 5 days, d42-donor CD8+ T cells recovered from B6 mice with ongoing GVHD survived over 5 days in the presence of IL-2+IL-15 alone and these surviving d42-CD8+ T cells were able to rapidly proliferate in responding to B6 DCs+IL-2+IL-15 in secondary culture. Flow cytometry analysis showed that d42-CD8+ T cells contained at least two distinct subsets: CD44hiCD62Llo (80% to 85%) and CD44hiCD62LhiCD8+(3% to 6%) T cells, resembling to the phenotype of effector memory and central memory CD8+ T cells, respectively. Administration of irradiated secondary B6 mice with either d42-CD44hiCD62Lhi or d42-CD44hiCD62Llo CD8+ T cell subset recovered at day 42 from primary B6 mice receiving C3H.SW CD44loCD8+ T cells + T−BM caused virulent GVHD. These results indicate that alloreactive memory T cells develop in vivo in recipient mice with acute GVHD where host mHAs persist and may be responsible for the persistence of GVHD. Accordingly, we suggest that in vivo blockade of both alloreactive effector and memory T cell responses will be necessary for GVHD prevention and treatment.

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

2007 ◽  
Vol 178 (4) ◽  
pp. 2296-2306 ◽  
Author(s):  
Cristina F. Arias ◽  
André Ballesteros-Tato ◽  
María Isabel García ◽  
Juan Martín-Caballero ◽  
Juana M. Flores ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
T Cell Responses ◽  
Memory T Cell ◽  
Cell Responses

scholarly journals CD4+ and CD8+ Circulating Memory T Cells Are Crucial in the Protection Induced by Vaccination with Salmonella Typhi Porins

2021 ◽  
Vol 9 (4) ◽  
pp. 770
Author(s):  
Luis Ontiveros-Padilla ◽  
Alberto García-Lozano ◽  
Araceli Tepale-Segura ◽  
Tania Rivera-Hernández ◽  
Rodolfo Pastelin-Palacios ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Salmonella Typhi ◽  
Effector Memory ◽  
Functional Responses ◽  
Memory Phenotype ◽  
Memory T Cell ◽  
Cell Responses

Salmonella enterica serovar Typhi (S. Typhi) porins, OmpC and OmpF, are potent inducers of the immune response against S. Typhi in mice and humans. Vaccination with porins induces the protection against 500 LD50 of S. Typhi, life-lasting bactericidal antibodies and effector T cell responses in mice; however, the nature of the memory T cell compartment and its contribution to protection remains unknown. In this work, we firstly observed that vaccination with porins induces in situ (skin) CD4+ and CD8+ T cell responses. Analysis of the porin-specific functional responses of skin CD4+ and CD8+ T cells showed IFN-gamma- and IL-17-producing cells in both T cell populations. The memory phenotype of porin-specific T cells indicated the presence of resident and effector memory phenotypes in the skin, and a central memory phenotype in the skin-draining lymph node. In addition, we demonstrated that vaccination with porins via skin reduces the bacterial burden following challenge. Finally, evaluating the role of the circulating T cell memory population in protection, we showed that circulating memory CD4+ and CD8+ T cells are crucial in porin-mediated protection against S. Typhi. Overall, this study highlights the importance of inducing circulating memory T cell responses in order to achieve the optimal protection provided by porins, showing a mechanism that could be sought in the rational development of vaccines.

scholarly journals Optimising T cell (re)boosting strategies for adenoviral and modified vaccinia Ankara vaccine regimens in humans

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Stefania Capone ◽  
Anthony Brown ◽  
Felicity Hartnell ◽  
Mariarosaria Del Sorbo ◽  
Cinzia Traboni ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Viral Vectors ◽  
Standard Dose ◽  
T Cell Responses ◽  
Effector Memory ◽  
Cell Responses ◽  
Wide Range

Abstract Simian adenoviral and modified vaccinia Ankara (MVA) viral vectors used in heterologous prime-boost strategies are potent inducers of T cells against encoded antigens and are in advanced testing as vaccine carriers for a wide range of infectious agents and cancers. It is unclear if these responses can be further enhanced or sustained with reboosting strategies. Furthermore, despite the challenges involved in MVA manufacture dose de-escalation has not been performed in humans. In this study, healthy volunteers received chimpanzee-derived adenovirus-3 and MVA vaccines encoding the non-structural region of hepatitis C virus (ChAd3-NSmut/MVA-NSmut) 8 weeks apart. Volunteers were then reboosted with a second round of ChAd3-NSmut/MVA-NSmut or MVA-NSmut vaccines 8 weeks or 1-year later. We also determined the capacity of reduced doses of MVA-NSmut to boost ChAd3-NSmut primed T cells. Reboosting was safe, with no enhanced reactogenicity. Reboosting after an 8-week interval led to minimal re-expansion of transgene-specific T cells. However, after a longer interval, T cell responses expanded efficiently and memory responses were enhanced. The 8-week interval regimen induced a higher percentage of terminally differentiated and effector memory T cells. Reboosting with MVA-NSmut alone was as effective as with ChAd3-NSmut/MVA-NSmut. A ten-fold lower dose of MVA (2 × 107pfu) induced high-magnitude, sustained, broad, and functional Hepatitis C virus (HCV)-specific T cell responses, equivalent to standard doses (2 × 108 pfu). Overall, we show that following Ad/MVA prime-boost vaccination reboosting is most effective after a prolonged interval and is productive with MVA alone. Importantly, we also show that a ten-fold lower dose of MVA is as potent in humans as the standard dose.

scholarly journals Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mariana Guerra-Maupome ◽  
Jodi L. McGill
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Memory Cell ◽  
Effector Memory ◽  
Γδ T Cell ◽  
Respiratory Mucosa ◽  
Bcg Vaccination ◽  
Cell Responses

Abstract The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.

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