scholarly journals Normal Numbers of Stem Cell Memory T Cells Despite Strongly Reduced Naive T Cells Support Intact Memory T Cell Compartment in Ataxia Telangiectasia

2021 ◽  
Vol 12 ◽  
Author(s):  
Thomas J. Weitering ◽  
Janine E. Melsen ◽  
Monique M. van Ostaijen-ten Dam ◽  
Corry M. R. Weemaes ◽  
Marco W. Schilham ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Ataxia Telangiectasia ◽  
Memory T Cells ◽  
Spectral Flow ◽  
Normal Numbers ◽  
Cell Compartment ◽  
Cell Memory ◽  
Memory T Cell

Ataxia Telangiectasia (AT) is a rare inherited disorder characterized by progressive cerebellar ataxia, chromosomal instability, cancer susceptibility and immunodeficiency. AT is caused by mutations in the ATM gene, which is involved in multiple processes linked to DNA double strand break repair. Immunologically, ATM mutations lead to hampered V(D)J recombination and consequently reduced numbers of naive B and T cells. In addition, class switch recombination is disturbed resulting in antibody deficiency causing common, mostly sinopulmonary, bacterial infections. Yet, AT patients in general have no clinical T cell associated infections and numbers of memory T cells are usually normal. In this study we investigated the naive and memory T cell compartment in five patients with classical AT and compared them with five healthy controls using a 24-color antibody panel and spectral flow cytometry. Multidimensional analysis of CD4 and CD8 TCRαβ+ cells revealed that early naive T cell populations, i.e. CD4+CD31+ recent thymic emigrants and CD8+CCR7++CD45RA++ T cells, were strongly reduced in AT patients. However, we identified normal numbers of stem cell memory T cells expressing CD95, which are antigen-experienced T cells that can persist for decades because of their self-renewal capacity. We hypothesize that the presence of stem cell memory T cells explains why AT patients have an intact memory T cell compartment. In line with this novel finding, memory T cells of AT patients were normal in number and expressed chemokine receptors, activating and inhibitory receptors in comparable percentages as controls. Comparing memory T cell phenotypes by Boolean gating revealed similar diversity indices in AT compared to controls. We conclude that AT patients have a fully developed memory T cell compartment despite strongly reduced naive T cells. This could be explained by the presence of normal numbers of stem cell memory T cells in the naive T cell compartment, which support the maintenance of the memory T cells. The identification of stem cell memory T cells via our spectral flow cytometric approach is highly relevant for better understanding of T cell immunity in AT. Moreover, it provides possibilities for further research on this recently identified T cell population in other inborn errors of immunity.

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.

A Rare Population of Stem Cell Memory T Cells is an Apex of the Hierarchy of Adult T-Cell Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3001-3001
Author(s):  
Yuya Nagai ◽  
Masahiro Kawahara ◽  
Masakatsu Hishizawa ◽  
Noriko Sugino ◽  
Yayoi Shimazu ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Memory T Cells ◽  
Inverse Pcr ◽  
Cell Leukemia ◽  
Cell Memory ◽  
Adult T Cell Leukemia ◽  
Original Clone ◽  
Infected Cells

Abstract Adult T-cell leukemia (ATL) is a mature T cell neoplasm causatively associated with HTLV-1. It takes a long period, around 50 years, to develop ATL after the transmission of HTLV-1 in infancy through breastfeeding, suggesting the pool for the generation of ATL clone may exist somewhere. Recent reports showed human CD34+ bone marrow cells infected by HTLV-1 ex vivo can generate CD4+ T-cell lymphomas in immunodeficiency mice or that CD117+ early hematopoietic progenitors can develop lymphoma in transgenic mice model of Tax which is an oncogenic protein of HTLV-1. These results suggest the model of leukemia initiating cells, that leukemia is organized hierarchically and sustained by a small subset of stem/progenitors at the apex, might be acceptable in ATL. A more recent report demonstrated that a novel compartment of normal T cells, termed stem cell memory T cells (TSCM), possesses stem cell-like capacity including relatively enhanced self-renewal capacity and multipotent ability to generate all memory and effector T cell subsets. This concept prompts us to hypothesize that TSCM subset might contribute to the development of ATL. First, to investigate whether hematopoietic stem/progenitor cells in primary samples of ATL patients are infected with HTLV-1, we sorted lineage(CD3, CD4, CD8, CD11b, CD14, CD19, CD20, CD56, CD235)-negative CD34+ cells from bone marrow samples of ATL patients by FACS AriaII, purified genomic DNA, and then performed PCR of pX region which is a virus specific gene. No amplification of pX was detected in all samples we studied. Next, to focus on TSCM population, we established the eight-color staining method with lineage of NK/Monocyte/DC (CD11b, CD14 and CD56), CD4, CD45RA, CD45RO, CCR7, CD95, CD122 and CD25. We successfully separated CD4+ T cells from ATL patients into four subsets; naïve T (TN: CD4+CD45RA+CD45RO-CCR7+CD95-CD122-), stem cell memory T (TSCM: CD4+CD45RA+CD45RO-CCR7+CD95+CD122dim), central memory T (TCM: CD4+CD45RA-CD45RO+CCR7+), and effector memory T (TEM: CD4+CD45RA-CD45RO+CCR7-). Although ATL cells are generally CD45RO positive, so that TCM and TEM were extremely dominant, CD45RA positive populations did exist in all ATL samples we studied. To assess the frequency of infected cells, we performed quantitative PCR with the sensitivity of 5 copies detectable at the minimum and calculated by dividing copy number of pX in HTLV-1 provirus with that of RNase P in human genome in genomic DNA from 1,000 cells of each subset. Almost all cells in TCM and TEM and more than 10% of cells in TSCM were infected in most of cases while none of infected cells were detected in TN in our experiment design. Since ATL is caused by monoclonal expansion from plenty of HTLV-1 infected clones, we focused on the existence of ATL original clone in each subset. We determined the ATL original clone by inverse PCR and the clone-specific provirus integration site by sequencing of the inverse PCR product in each case, and then constructed PCR primers being capable of detecting each ATL original clone by regular PCR. Interestingly we found each ATL clone was detected in TSCM, TCM, and TEM but not in TN subset in all studied cases, indicating TSCM could be an origin of ATL cells. To investigate whether there is a hierarchy in ATL cells, we next performed in vitro culture with IL-7 and examined the status of CD45RA and CCR7 after 2 weeks. Intriguingly TSCM generated TCM and TEM while TCM and TEM did not generate TSCM, suggesting TSCM is an apex in HTLV-1 infected T cells. To investigate tumorigenicity of TSCM, we adopted xenogeneic transplantation assay. When we inoculated 3x104 cells of each subset from one ATL patient into immune deficient mice (NOG mice) intraperitoneally, we observed high number of cells in peripheral blood and spleen of recipient mice transplanted with TSCM compared to TCM and TEM. Phenotypically TCM and TEM were generated in mice transplanted with TSCM as well as TCM and TEM while TSCM was only generated from TSCM but not TCM and TEM. Furthermore we analyzed the clonality of engrafted cells by ATL clone-specific PCR and inverse PCR, and found that the patient original clone becomes dominant in recipient mice inoculated with TSCM but not in those with TCM and TEM. Taken together, our findings provide new insights that TSCM could be an apex of the hierarchy of ATL and play an important role in development and maintenance of ATL clone. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1749-1754 ◽  
Author(s):  
W. Nicholas Haining ◽  
Donna S. Neuberg ◽  
Heather L. Keczkemethy ◽  
John W. Evans ◽  
Stephen Rivoli ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Protective Immunity ◽  
Memory T Cells ◽  
Lymphoblastic Leukemia ◽  
T Cell Memory ◽  
Cell Compartment ◽  
Cell Memory ◽  
Cell Numbers

Abstract Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured T-cell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand pre-existing memory T cells. (Blood. 2005; 106:1749-1754)

scholarly journals Differences in coreceptor specificity contribute to alternative tropism of HIV-1 subtype C for CD4+T-cell subsets, including stem cell memory T-cells

Retrovirology ◽  
2014 ◽  
Vol 11 (1) ◽  
Author(s):  
Kieran Cashin ◽  
Geza Paukovics ◽  
Martin R Jakobsen ◽  
Lars Østergaard ◽  
Melissa J Churchill ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Subtype C ◽  
Cell Memory ◽  
Hiv 1

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 T cell–derived interferon-γ programs stem cell death in immune-mediated intestinal damage

2019 ◽  
Vol 4 (42) ◽  
pp. eaay8556 ◽  
Author(s):  
S. Takashima ◽  
M. L. Martin ◽  
S. A. Jansen ◽  
Y. Fu ◽  
J. Bos ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Paneth Cell ◽  
Interferon Γ ◽  
Cell Compartment ◽  
Stem Cell Compartment ◽  
Immune Mediated ◽  
Donor T Cells ◽  
Epithelial Cultures

Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance, there is limited understanding of how immune-mediated damage affects ISCs and their niche. We found that stem cell compartment injury is a shared feature of both alloreactive and autoreactive intestinal immunopathology, reducing ISCs and impairing their recovery in T cell–mediated injury models. Although imaging revealed few T cells near the stem cell compartment in healthy mice, donor T cells infiltrating the intestinal mucosa after allogeneic bone marrow transplantation (BMT) primarily localized to the crypt region lamina propria. Further modeling with ex vivo epithelial cultures indicated ISC depletion and impaired human as well as murine organoid survival upon coculture with activated T cells, and screening of effector pathways identified interferon-γ (IFNγ) as a principal mediator of ISC compartment damage. IFNγ induced JAK1- and STAT1-dependent toxicity, initiating a proapoptotic gene expression program and stem cell death. BMT with IFNγ–deficient donor T cells, with recipients lacking the IFNγ receptor (IFNγR) specifically in the intestinal epithelium, and with pharmacologic inhibition of JAK signaling all resulted in protection of the stem cell compartment. In addition, epithelial cultures with Paneth cell–deficient organoids, IFNγR-deficient Paneth cells, IFNγR–deficient ISCs, and purified stem cell colonies all indicated direct targeting of the ISCs that was not dependent on injury to the Paneth cell niche. Dysregulated T cell activation and IFNγ production are thus potent mediators of ISC injury, and blockade of JAK/STAT signaling within target tissue stem cells can prevent this T cell–mediated pathology.

scholarly journals Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate

2020 ◽  
Vol 32 (9) ◽  
pp. 571-581 ◽  
Author(s):  
Shiki Takamura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Primary Immune Response ◽  
Memory T Cell ◽  
Cognate Antigen ◽  
Memory Cd8 T Cell

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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