scholarly journals Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells

2009 ◽  
Vol 206 (7) ◽  
pp. 1525-1534 ◽  
Author(s):  
Rebekka Geiger ◽  
Thomas Duhen ◽  
Antonio Lanzavecchia ◽  
Federica Sallusto
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Processing ◽  
Cellular Immunotherapy ◽  
Maximal Response ◽  
T Cell Clones ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Mhc Molecules ◽  
Cell Clones

The enormous diversity of the naive T cell repertoire is instrumental in generating an immune response to virtually any foreign antigen that can be processed into peptides that bind to MHC molecules. The low frequency of antigen-specific naive T cells, their high activation threshold, and the constrains of antigen-processing and presentation have hampered analysis of naive repertoires to complex protein antigens. In this study, libraries of polyclonally expanded naive T cells were used to determine frequency and antigen dose–response of human naive CD4+ T cells specific for a variety of antigens and to isolate antigen-specific T cell clones. In the naive repertoire, T cells specific for primary antigens, such as KLH and Bacillus anthracis protective antigen, and for recall antigens, such as tetanus toxoid, cytomegalovirus, and Mycobacterium tuberculosis purified protein derivative, were detected at frequencies ranging from 5 to 170 cells per 106 naive T cells. Antigen concentrations required for half-maximal response (EC50) varied over several orders of magnitude for different naive T cells. In contrast, in the memory repertoire, T cells specific for primary antigens were not detected, whereas T cells specific for recall antigens were detected at high frequencies and displayed EC50 values in the low range of antigen concentrations. The method described may find applications for evaluation of vaccine candidates, for testing antigenicity of therapeutic proteins, drugs, and chemicals, and for generation of antigen-specific T cell clones for adoptive cellular immunotherapy.

scholarly journals Anti-IE1 CD4+ T-cell clones kill peptide-pulsed, but not human cytomegalovirus-infected, target cells

2007 ◽  
Vol 88 (9) ◽  
pp. 2441-2449 ◽  
Author(s):  
Sandra Delmas ◽  
Pierre Brousset ◽  
Danièle Clément ◽  
Emmanuelle Le Roy ◽  
Jean-Luc Davignon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Antigen Processing ◽  
Hcmv Infection ◽  
Target Cells ◽  
T Cell Clones ◽  
Early Protein ◽  
Cell Clones ◽  
Precise Role

Cellular immunity plays a major role in the control of human cytomegalovirus (HCMV) infection. CD4+ T lymphocytes have been shown to contribute to this function but their precise role is a matter of debate. Although CD4+ T cells have been shown to kill target cells through the perforin/granzyme pathway, whether HCMV-specific CD4+ T cells are capable of killing HCMV-infected targets has not yet been documented. In the present paper, we have taken advantage of well established cellular reagents to address this issue. Human CD4+ T-cell clones specific for the major immediate-early protein IE1 were shown to perform perforin-based cytotoxicity against peptide-pulsed targets. However, when tested on infected anitgen presenting cell targets, cytotoxicity was not detectable, although gamma interferon (IFN-γ) production was significant. Furthermore, cytotoxicity against peptide-pulsed targets was inhibited by HCMV infection, whereas IFN-γ production was not modified, suggesting that antigen processing was not altered. Remarkably, degranulation of CD4+ T cells in the presence of infected targets was significant. Together, our data suggest that impaired cytotoxicity is not due to failure to recognize infected targets but rather to a mechanism specifically related to cytotoxicity.

scholarly journals Cell generation dynamics underlying naïve T cell homeostasis in adult humans

2019 ◽  
Author(s):  
Jeff E. Mold ◽  
Pedro Réu ◽  
Axel Olin ◽  
Samuel Bernard ◽  
Jakob Michaëlsson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Turnover ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Age Related ◽  
Cell Clones ◽  
Naïve T Cell ◽  
Cd31 Expression ◽  
Naive T Cell

ABSTRACTThymic involution and proliferation of naive T cells both contribute to shaping the naive T cell repertoire as humans age, but a clear understanding of the roles of each throughout a human lifespan has been difficult to determine. By measuring nuclear bomb test-derived14C in genomic DNA we determined the turnover rates of CD4+and CD8+naïve T cell populations and defined their dynamics in healthy individuals ranging from 20-65 years of age. We demonstrate that naïve T cell generation decreases with age, and that this could be explained by a combination of declining cell loss, peripheral division and thymic production during adulthood. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of naïve T cell turnover using mass cytometry to profile candidate signaling pathways involved in T cell activation and proliferation in CD4+naive T cells relative to CD31 expression, a marker of thymic proximity. We show that basal NF-κB phosphorylation inversely correlated with CD31 expression and thus is decreased in peripherally expanded naive T cell clones. Functionally we found that NF-κB signaling was essential for naive T cell proliferation to the homeostatic growth factor IL-7, and reduced NF-κB phosphorylation in CD4+CD31−naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naïve T cell turnover as a putative regulator of naïve T cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T cell clones that accumulate with age.

Shedding Light on Drug-Induced Liver Injury: Activation of T Cells From Drug Naive Human Donors With Tolvaptan and a Hydroxybutyric Acid Metabolite

2020 ◽  
Author(s):  
Sean Hammond ◽  
Andrew Gibson ◽  
Kanoot Jaruthamsophon ◽  
Sharin Roth ◽  
Merrie Mosedale ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Injury ◽  
Antigen Processing ◽  
Hydroxybutyric Acid ◽  
T Cell Clones ◽  
Adaptive Immune ◽  
Cell Clones ◽  
T Cell Clone ◽  
Immune Attack

Abstract Exposure to tolvaptan is associated with a significant risk of liver injury in a small fraction of patients with autosomal dominant polycystic kidney disease. The observed delayed onset of liver injury of between 3 and 18 months after commencing tolvaptan treatment, along with rapid recurrence of symptoms following re-challenge is indicative of an adaptive immune attack. This study set out to assess the intrinsic immunogenicity of tolvaptan and pathways of drug-specific T-cell activation using in vitro cell culture platforms. Tolvaptan (n = 7), as well as oxybutyric (DM-4103, n = 1) and hydroxybutyric acid (DM-4107, n = 18) metabolite-specific T-cell clones were generated from tolvaptan naive healthy donor peripheral blood mononuclear cells. Tolvaptan and DM-4103 T-cell clones could also be activated with DM-4107, whereas T-cell clones originally primed with DM-4107 were highly specific to this compound. A signature cytokine profile (IFN-γ, IL-13, granzyme B, and perforin) for almost all T-cell clones was identified. Mechanistically, compound-specific T-cell clone activation was dependent on the presence of soluble drug and could occur within 4 h of drug exposure, ruling out a classical hapten mechanism. However, antigen processing dependence drug presentation was indicated in many T-cell clones. Collectively these data show that tolvaptan-associated liver injury may be attributable to an adaptive immune attack upon the liver, with tolvaptan- and metabolite-specific T cells identified as candidate effector cells in such etiology.

scholarly journals Long-Term Depletion of Naive T Cells in Patients Treated for Hodgkin's Disease

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3662-3672 ◽  
Author(s):  
Nobukazu Watanabe ◽  
Stephen C. De Rosa ◽  
Anthony Cmelak ◽  
Richard Hoppe ◽  
Leonore A. Herzenberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Counts

Abstract We investigated the representation of T cells in patients who had been treated for Hodgkin's disease (HD). We found a marked depletion in both CD4 and CD8 naive T-cell counts that persists up to 30 years after completion of treatment. In contrast, CD4 and CD8 memory T-cell subsets recovered to normal or above normal levels by 5 years posttreatment. Thus, the previously-reported long-term deficit in total CD4 T-cell counts after treatment for HD is due to specific depletion of naive T cells. Similarly, total CD8 T-cell counts return to normal by 5 years only because CD8 memory T cells expand to higher than normal levels. These findings suggest that the treatment (mediastinal irradiation) results in a longterm dysregulation of T-cell subset homeostasis. The profound depletion of naive T cells may explain the altered T-cell function in treated patients, including the poor response to immunization after treatment for HD. Further, in some individuals, we identified expansions of unusual subsets expressing low levels of CD8. Eight-color fluorescence-activated cell sorting analyses showed that these cells largely express CD8αα homodimers and CD57, consistent with the phenotype of potentially extrathymically derived T cells. In addition, these cells, both CD4+ and CD4−, are probably cytotoxic lymphocytes, as they express high levels of intracellular perforin. In adults treated for HD, an increased activity of extrathymic T-cell differentiation may partially compensate for the loss of thymic-derived T cells.

scholarly journals VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

Science ◽  
2020 ◽  
Vol 367 (6475) ◽  
pp. eaay0524 ◽  
Author(s):  
Mohamed A. ElTanbouly ◽  
Yanding Zhao ◽  
Elizabeth Nowak ◽  
Jiannan Li ◽  
Evelien Schaafsma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Subset ◽  
Peripheral Tolerance ◽  
Cell Immune Response ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naïve T Cell ◽  
Naive T Cell

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

scholarly journals Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

1992 ◽  
Vol 176 (5) ◽  
pp. 1431-1437 ◽  
Author(s):  
M Croft ◽  
D D Duncan ◽  
S L Swain
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 Cells ◽  
Peptide Antigen ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

Abstract 424: Effector T Cells Induce Cardiac Fibroblasts Transition to Myofibroblasts & Contribute to Pressure Overload Induced Cardiac Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tania A Nevers ◽  
Ane Salvador ◽  
Francisco Velazquez ◽  
Mark Aronovitz ◽  
Robert Blanton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Effector T Cell ◽  
Naïve T Cells

Background: Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. Recently, we showed that T cell deficient mice (TCRα -/- ) do not develop cardiac fibrosis (CF) and have preserved cardiac function in the thoracic aortic constriction (TAC) mouse model of pressure overload (PO). Specifically, CD4 + T cells are activated in the cardiac draining lymph nodes and infiltrate the LV, where the Th1 and Th17 effector T cell signature transcription factors are significantly upregulated as compared with control mice. However, the T cell subsets involved and the mechanisms by which they contribute to CF and pathogenesis of non-ischemic HF remains to be determined. Thus, we hypothesize that heart infiltrated effector T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix-producing cardiac myofibroblasts. Methods and Results: Naïve or effector T cells differentiated in vitro or isolated from mice undergoing TAC or Sham surgery were co-cultured with adult C57BL/6 cardiac fibroblasts (CFB). In contrast with naïve T cells, effector T cells and PO activated T cells strongly adhered to CFB and mediated fibroblast to myofibroblasts transition as depicted by immunofluorescence expression of SMAα. Effector T cell supernatants only slightly mediated this transition, indicating that effector T cells direct contact with CFB, rather than cytokine release is required to mediate CFB transformation. Adoptive transfer of effector, but not naïve T cells, into TCRα -/- recipient mice in the onset of TAC resulted in T cells infiltration into the left ventricle and increased CF. Conclusions: Our data indicate that CD4+ effector T cells directly interact with CFB to induce CF in response to PO induced CF. Future studies will determine the adhesion mechanisms regulating this crosstalk and evaluate the pro-fibrotic mechanisms induced and whether this is a T effector cell specific subset. These results will provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of CF in non- ischemic HF.

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