scholarly journals Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression

2020 ◽  
Author(s):  
Aparna Nathan ◽  
Jessica I. Beynor ◽  
Yuriy Baglaenko ◽  
Sara Suliman ◽  
Kazuyoshi Ishigaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Surface Proteins ◽  
Effector Memory ◽  
Specific Cell ◽  
Memory State ◽  
Memory T Cell ◽  
Cell State

AbstractMycobacterium tuberculosis (M.tb) results in 10 million active tuberculosis (TB) cases and 1.5 million deaths each year1, making it the world’s leading infectious cause of death2. Infection leads to either an asymptomatic latent state or TB disease. Memory T cells have been implicated in TB disease progression, but the specific cell states involved have not yet been delineated because of the limited scope of traditional profiling strategies. Furthermore, immune activation during infection confounds underlying differences in T cell state distributions that influence risk of progression. Here, we used a multimodal single-cell approach to integrate measurements of transcripts and 30 functionally relevant surface proteins to comprehensively define the memory T cell landscape at steady state (i.e., outside of active infection). We profiled 500,000 memory T cells from 259 Peruvians > 4.7 years after they had either latent M.tb infection or active disease and defined 31 distinct memory T cell states, including a CD4+CD26+CD161+CCR6+ effector memory state that was significantly reduced in patients who had developed active TB (OR = 0.80, 95% CI: 0.73–0.87, p = 1.21 × 10−6). This state was also polyfunctional; in ex vivo stimulation, it was enriched for IL-17 and IL-22 production, consistent with a Th17-skewed phenotype, but also had more capacity to produce IFNγ than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection.

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.

Ex Vivo Fludarabine Selectively Depletes Human Naive T-Cell Subsets: A Step Toward Modifying Donor Lymphocyte Infusion.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1071-1071
Author(s):  
Melody M. Smith ◽  
Cynthia R. Giver ◽  
Edmund K. Waller ◽  
Christopher R. Flowers
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Ex vivo modification of donor lymphocytes with purine analogs (mDL) may help to minimize graft versus host disease (GvHD) while providing beneficial graft versus leukemia (GvL) effects. In a murine model system, we have shown that allogeneic donor splenocytes, treated with fludarabine ex vivo have significantly reduced GvHD activity when transferred to irradiated recipient mice, and retain anti-viral and GvL activities (Giver, 2003). This effect appears to be mediated by relative depletion of donor CD4 CD44low, “naive” T-cells. As a first step toward developing mDL for use in patients, we sought to evaluate the effects of ex vivo fludarabine exposure on human T-cell subsets, and to determine the minimum dose of fludarabine required to achieve this effect. Methods: Peripheral blood mononuclear cell samples from 6 healthy volunteers were evaluated at 0, 24, 48, and 72 hour time points after ex vivo incubation in varying dosages of fludarabine: 2, 5, and 10(n=3) mcg/ml. Fludarabine incubated samples were compared to samples that received no fludarabine (untreated). The total viable cell number was determined and the fractions and absolute numbers of viable CD4 and CD8 naïve and memory T-cells were determined using flow cytometry after incubation with 7-AAD (dead cell stain), CD4, CD8, CD45RA, CD62L, and CCR7 antibodies, and measuring the total viable cells/ml. Results: The numbers of viable CD4 and CD8 T-cells remained relatively stable in control cultures. Without fludarabine, the average viability at 72 hr of naive and memory T-cells were 92% and 77% for CD4 and 86% and 63% for CD 8 (Fig. 1A). Naive CD4 T-cells were more sensitive to fludarabine-induced death than memory CD4 cells. At 72 hr, the average viability of fludarabine-treated naive CD4 T-cells was 33% at 2 mcg/ml (8.2X the reduction observed in untreated cells) and 30% at 5 mcg/ml, while memory CD4 T-cells averaged 47% viability at 2 mcg/ml (2.3X the reduction observed in untreated cells) (Fig. 1B) and 38% at 5 mcg/ml. The average viability of naive CD8 T-cells at 72 hr was 27% at 2 mcg/ml and 20% at 5 mcg/ml, while memory CD8 T-cell viability was 22% at 2 mcg/ml and 17% at 5 mcg/ml. Analyses on central memory, effector memory, and Temra T-cells, and B-cell and dendritic cell subsets are ongoing. The 5 and 10 mcg/ml doses also yielded similar results in 3 initial subjects, suggesting that 2 mcg/ml or a lower dose of fludarabine is sufficient to achieve relative depletion of the naive T-cell subset. Conclusions: Future work will determine the minimal dose of fludarabine to achieve this effect, test the feasibility of using ex vivo nucleoside analog incubation to reduce alloreactivity in samples from patient/donor pairs, and determine the maximum tolerated dose of mDL in a phase 1 clinical trial with patients at high risk for relapse and infectious complications following allogeneic transplantation. Figure Figure

scholarly journals Initiation of Antiretroviral Therapy Restores CD4+T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

2016 ◽  
Vol 90 (15) ◽  
pp. 6699-6708 ◽  
Author(s):  
Emily K. Cartwright ◽  
David Palesch ◽  
Maud Mavigner ◽  
Mirko Paiardini ◽  
Ann Chahroudi ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Lymph Nodes ◽  
Memory T Cells ◽  
Effector Memory ◽  
Ki 67 ◽  
Memory T Cell ◽  
Immunodeficiency Virus

ABSTRACTTreatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4+T memory stem cells (TSCM) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4+TSCMare preserved in number but show (i) a decrease in the frequency of CCR5+cells, (ii) an expansion of the fraction of proliferating Ki-67+cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4+TSCMhomeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4+CCR5+TSCMboth in blood and in lymph nodes and a reduction in the fraction of proliferating CD4+Ki-67+TSCMin blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4+transitional memory (TTM) and effector memory (TEM) T cells declined ∼100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4+TSCMand central memory T cells (TCM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4+TSCMhomeostasis, and the observed stable level of virus in TSCMsupports the hypothesis that these cells are a critical contributor to SIV persistence.IMPORTANCEUnderstanding the roles of various CD4+T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (TSCM) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (TCMand TTM, respectively). CD4+TSCMare disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4+TSCMhomeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as TTMand effector memory (TEM). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4+TSCMduring suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir.

CXCR3 Is Required for the Efficient Recruitment of Bone Marrow-Resident Memory T Cells to Inflamed Tissues,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3242-3242
Author(s):  
Robbert van der Voort ◽  
Claudia Brandao ◽  
Thomas J. Volman ◽  
Viviènne Verweij ◽  
Klaas van Gisbergen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell

Abstract Abstract 3242 Although the importance of the bone marrow (BM) in hematopoiesis is well known, its function in adaptive immune responses has only recently been acknowledged. Currently it is known that the BM contains fully functional CD4+ and CD8+ T cells that can engage in both primary and secondary immune responses. Interestingly, most of these T cells belong to the memory T cell lineage, identifying the BM as one of the largest memory T cell reservoirs in the body. Since not much is known about the trafficking of BM T cells, we compared the homing phenotype and function of T cell subsets in the BM, blood, spleen and peripheral lymph nodes (pLN). In addition, we determined the expression of chemokine mRNA and protein levels in the BM and other lymphoid organs. We confirmed that at least 80% of the CD4+ and 60% of the CD8+ BM T cells have a memory phenotype, and that most CD4+ T cells belong to the effector memory lineage, while the CD8+ population predominantly consists of central memory T cells. Most BM T cells expressed the chemokine receptor CXCR3, the adhesion molecules P-selectin glycoprotein ligand 1 and VLA-4, and increased levels of CD44 and LFA-1, as compared to T cells from the spleen. In addition, L-selectin was absent from most CD4+ BM T cells, but present on virtually all CD8+ T cells. Notably, the percentage of CXCR3+ T cells within the effector memory and central memory subsets from BM was higher than within the same subsets from pLN. Furthermore, BM contained significant mRNA levels of the CXCR3 ligands CXCL9, CXCL10 and CXCL11. An in vivo migration assay using a mixture of fluorescent-labeled T cells from CXCR3-deficient mice and control mice indicated however that during homeostasis CXCR3 does not play a major role in BM entry or retention. These data suggest that CXCR3 expressed by memory T cells is rather involved in BM exit, than in BM entry. Indeed, we observed that, as compared to control mice, CXCR3−/− mice contained significantly more CD4+ and CD8+ T cells in their BM. Additional in vitro assays demonstrated that CD4+ and CD8+ BM T cells migrated vigorously in response to CXCL9 and CXCL10, generally released in high concentrations during inflammation. Finally, we demonstrate that CXCR3−/− effector/effector memory T cells, but not wild type T cells, accumulate in the BM of mice infected with lymphocytic choriomeningitis virus. Altogether, these data demonstrate that the BM is a major reservoir of memory T cells that employ CXCR3 to quickly respond to chemotactic signals from inflamed tissues. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The CD8+ memory T-cell state of readiness is actively maintained and reversible

Blood ◽  
2009 ◽  
Vol 114 (10) ◽  
pp. 2121-2130 ◽  
Author(s):  
Atef Allam ◽  
Dietrich B. Conze ◽  
Maria Letizia Giardino Torchia ◽  
Ivana Munitic ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Memory T Cells ◽  
Tumor Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Memory Cells ◽  
Memory State ◽  
Memory T Cell

AbstractThe ability of the adaptive immune system to respond rapidly and robustly upon repeated antigen exposure is known as immunologic memory, and it is thought that acquisition of memory T-cell function is an irreversible differentiation event. In this study, we report that many phenotypic and functional characteristics of antigen-specific CD8 memory T cells are lost when they are deprived of contact with dendritic cells. Under these circumstances, memory T cells reverted from G1 to the G0 cell-cycle state and responded to stimulation like naive T cells, as assessed by proliferation, dependence upon costimulation, and interferon-γ production, without losing cell surface markers associated with memory. The memory state was maintained by signaling via members of the tumor necrosis factor receptor superfamily, CD27 and 4-1BB. Foxo1, a transcription factor involved in T-cell quiescence, was reduced in memory cells, and stimulation of naive CD8 cells via CD27 caused Foxo1 to be phosphorylated and emigrate from the nucleus in a phosphatidylinositol-3 kinase–dependent manner. Consistent with these results, maintenance of G1 in vivo was compromised in antigen-specific memory T cells in vesicular stomatitis virus-infected CD27-deficient mice. Therefore, sustaining the functional phenotype of T memory cells requires active signaling and maintenance.

P1138FLOW CYTOMETRIC ANALYSIS ON LYMPHOCYTE SUBSETS APPEARED IN PERITONEAL DIALYSIS EFFLUENT IN RELATION WITH PERITONEAL FUNCTION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Atsuki Ohashi ◽  
Madoka Kondo ◽  
Fumitaka Ihara ◽  
Noriyuki Toshima ◽  
Yoshitatsu Ohara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Creatinine Ratio ◽  
Change Rate ◽  
Memory T Cell ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Background and Aims We previously reported that an increase of lymphocytes in peritoneal dialysis (PD) effluent was correlated with risk of encapsulating peritoneal sclerosis (EPS). In the present study, we analyzed subsets of lymphocytes in PD effluent by flow cytometry and evaluated their changes every six month to elucidate the etiological background of peritoneal dysfunction. Method We enrolled patients who started PD between 2006 and 2017, and of whom the data for PET and flow cytometric analysis was available at least for three consecutive times with an interval of six months. We excluded the patients who experienced PD peritonitis during the observation period. Consequently, the levels and changes of lymphocyte subset, such as CD4+/CD8+ naïve T cell (CCR7+/CD45RA+), CD4+/CD8+ central memory T cell (CCR7+/CD45RA-), CD4+/CD8+ effector memory T cell (CCR7-/CD45RA-), CD4+/CD8+ terminally differentiated effector memory T cell (CCR7-/CD45RA+), D/P creatinine ratio, FSC ratio of mesothelial cells and lymphocytes (a possible indicator for mesothelial cell size) were analysed in 23 patients over one year. Results We evaluated whether the observed variables on the first evaluation (six months after initiation of PD) affected the changes of D/P creatinine and FSC ratio over one year by a simple linear regression analysis. In the examined variables, only a fraction of CD8+ central memory T cell was significantly correlated with the change rate of D/P creatinine ratio (β=1.47, p=0.001, adjusted R2=0.379). We also evaluated whether the change rate of observed variables was correlated with the change rate of D/P creatinine and FSC ratio by a simple linear regression analysis. A fraction of CD8+ naïve T cell or CD8+ central memory cell was negatively correlated with the change rate of D/P creatinine ratio (naïve T cell; β=-0.058, p=0.022, adjusted R2=0.188, central memory T cell; β=-0.096, p=0.046, adjusted R2=0.137). The change rate of CD8+ effector memory T cell was not significantly correlated with the change rate of D/P creatinine ratio (β=0.172, p=0.096, adjusted R2=0.085). However, the change rate of D/P creatinine ratio tends to be higher in accordance with the increased change rate of CD8+ effector memory T cell by One way ANOVA, where the change rate was divided into three groups in descending order (p=0.0796) (Fig.1). Besides, the change rate of CD8+ effector memory T cell tends to be higher in accordance with the increased fraction of CD8+ central memory T cell at the first evaluation by Kruskall-Wallis test, where the change rate was divided into three groups in descending order (p=0.169) (Fig.2). Conclusion A decrease in the fraction of CD8+ naïve or central memory T cell was significantly correlated with the increase of D/P creatinine ratio. An Increase in the fraction of CD8+ effector memory T cell was also possibly correlated with the increase of D/P creatinine ratio, although it was not statistically significant (p=0.096). An initial fraction of CD8+ central memory T cell was significantly correlated with the change rate of D/P creatinine ratio. From these results, central memory T cells and naïve T cells at an initial stage may be transformed into effector memory T cells by repeated exposure to unknown antigens derived from PD solution and these effector memory T cells may damage the peritoneum to increase D/P creatinine ratio. An initial higher fraction of CD8+ central memory T cell suggested an acceleration in the transformation into CD8+ effector memory T cell.

scholarly journals Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

2007 ◽  
Vol 204 (7) ◽  
pp. 1665-1675 ◽  
Author(s):  
Sara Wojciechowski ◽  
Pulak Tripathi ◽  
Tristan Bourdeau ◽  
Luis Acero ◽  
H. Leighton Grimes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Critical Role ◽  
Normal Numbers ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Memory T Cell

We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.

scholarly journals Effect of Cyclophosphamide Treatment on Central and Effector Memory T Cells in Mice

2018 ◽  
Vol 37 (5) ◽  
pp. 373-382 ◽  
Author(s):  
Marcin Włodarczyk ◽  
Elżbieta Ograczyk ◽  
Magdalena Kowalewicz-Kulbat ◽  
Magdalena Druszczyńska ◽  
Wiesława Rudnicka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Immunosuppressive Agent ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Memory T Cell ◽  
Effector Memory T Cells ◽  
The Impact

Immunological memory is a key feature of adaptive immunity. It provides the organism with long-lived and robust protection against infection. The important question is whether cyclophosphamide (CP), as immunosuppressive agent used in cancer therapy and in some autoimmune diseases, may act on the memory T-cell population. We investigated the effect of CP on the percentage of central memory T cells (TCM) and effector memory T cells (TEM) in the mouse model of CP-induced immunosuppression (8-10-week-old male C57BL/6 mice CP treated for 7 days at the daily dose of 50 μg/g body weight [bw], manifested the best immunosuppression status, as compared to lower doses of CP: 10 or 20 μg/g bw). The CP induced a significant decrease in the percentage of CD8+ (TCM), compared to nonimmunosuppressed mice. This effect was not observed in the case of CD4+ TCM population. The percentage of gated TEM with CD4 and CD8 phenotype was significantly decreased in CP-treated mice, as compared to the control ones. Taken together, the above data indicate that CP-induced immunosuppression in mice leads to a reduction in the abundance of central memory cells possessing preferentially CD8+ phenotype as well as to a reduction in the percentage of effector memory cells (splenocytes both CD4+ and CD8+), compared to the cells from nonimmunosuppressed mice. These findings in mice described in this article may contribute to the understanding of the complexity of the immunological responses in humans and extend research on the impact of the CP model of immunosuppression in mice and memory T-cell populations.

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 Influence of age on functional memory T cell diversity

2021 ◽  
Author(s):  
Fengqin Fang ◽  
Wenqiang Cao ◽  
Weikang Zhu ◽  
Nora Lam ◽  
Lingjie Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Cell Subset ◽  
Surrogate Marker ◽  
T Cell Subsets ◽  
Immune Memory ◽  
Effector Memory ◽  
Memory T Cell ◽  
Cd73 Expression

Memory T cells exhibit considerable diversity that determines their ability to be protective and their durability. Here, we examined whether changes in T cell heterogeneity contribute to the age-associated failure of immune memory. By screening for age-dependent T cell surface markers, we have identified CD4 and CD8 memory T cell subsets that are unrelated to previously defined subsets of central and effector memory cells. Memory T cells expressing the ecto-5′-nucleotidase CD73 constitute a functionally distinct subset of memory T cells that declines with age. They exhibit many features favorable for immune protection, including longevity and polyfunctionality. They have a low turnover, but are poised to display effector functions and to develop into cells resembling tissue-resident memory T cells (TRM). Upstream regulators of differential chromatin accessibility and transcriptomes include transcription factors that are characteristic for conferring these superior memory features as well as facilitating CD73 expression. CD73 is not just a surrogate marker of these regulatory networks but is directly involved in T cell survival and TRM differentiation Interventions preventing the decline of this T cell subset or increasing CD73 expression have the potential to improve immune memory in older adults.

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