scholarly journals How heterogeneous thymic output and homeostatic proliferation shape naive T cell receptor clone abundance distributions

2019 ◽  
Author(s):  
Renaud Dessalles ◽  
Maria R. D’Orsogna ◽  
Tom Chou
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Homeostatic Proliferation ◽  
Abundance Distribution ◽  
Thymic Output ◽  
Immigration Process ◽  
Naïve T Cell ◽  
Naive T Cell ◽  
Birth Death

AbstractThe set of T cells that express the same T cell receptor (TCR) sequence represent a T cell clone. The number of different naive T cell clones in an organism reflects the number of different T cell receptors (TCRs) arising from recombination of the V(D)J gene segments during T cell development in the thymus. TCR diversity and more specifically, the clone abundance distribution is an important factor in immune function. Specific recombination patterns occur more frequently than others while subsequent interactions between TCRs and self-antigens are known to trigger proliferation and sustain naive T cell survival. These processes are TCR-dependent, leading to clone-dependent thymic export and naive T cell proliferation rates. Using a mean-field approximation to the solution of a regulated birth-death-immigration model, we systematically quantify how TCR-dependent heterogeneities in immigration and proliferation rates affect the shape of clone abundance distributions (the number of different clones that are represented by a specific number of cells). By comparing predicted clone abundances derived from our heterogeneous birth-death-immigration model with experimentally sampled clone abundances, we quantify the heterogeneity necessary to generate the observed abundances. Our findings indicate that heterogeneity in proliferation rates is more likely the mechanism underlying the observed clone abundance distributions than heterogeneity in immigration rates.Author SummaryThe abundance distribution of different T cell receptors (TCRs) expressed on naive T cells depends on their rates of thymic output, homeostatic proliferation, and death. However, measured TCR count distributions do not match, even qualitatively, those predicted from a multiclone birth death-immigration process when constant birth, death, and immigration rates are used (a neutral model). We show how non-neutrality in the birth-death-immigration process, where naive T cells with different TCRs are produced and proliferate with a distribution of rates shape the predicted sampled clone abundance distributions (the clone counts). Using physiological parameters, we find that heterogeneity in proliferation rates, and not in thymic output rates, is the main determinant in generating the observed clone counts. These findings are consistent with proliferation-driven maintenance of the T cell population in humans.

scholarly journals Naive T-cell receptor transgenic T cells help memory B cells produce antibody

Immunology ◽  
2006 ◽  
Vol 119 (3) ◽  
pp. 376-384 ◽  
Author(s):  
Darragh Duffy ◽  
Chun-Ping Yang ◽  
Andrew Heath ◽  
Paul Garside ◽  
Eric B. Bell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Memory B Cells ◽  
Naïve T Cell ◽  
Naive T Cell

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.

The lymphoid chemokine CCL21 costimulates naïve T cell expansion and Th1 polarization of non-regulatory CD4+ T cells

2004 ◽  
Vol 231 (1-2) ◽  
pp. 75-84 ◽  
Author(s):  
Kenneth Flanagan ◽  
Dorota Moroziewicz ◽  
Heesun Kwak ◽  
Heidi Hörig ◽  
Howard L. Kaufman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Expansion ◽  
T Cell Expansion ◽  
Th1 Polarization ◽  
Naïve T Cell ◽  
Naive T Cell

CMVpp65-Specific T cells generated from naïve T cell populations recognize atypical but not canonical epitopes and may be protective in Vivo

Cytotherapy ◽  
2015 ◽  
Vol 17 (6) ◽  
pp. S9-S10
Author(s):  
Patrick Hanley ◽  
Joseph Melenhorst ◽  
Russell Cruz ◽  
Caridad Martinez ◽  
Helen Heslop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Populations ◽  
Naïve T Cell ◽  
Naive T Cell

scholarly journals The Changing Landscape of Naive T Cell Receptor Repertoire With Human Aging

2018 ◽  
Vol 9 ◽  
Author(s):  
Evgeny S. Egorov ◽  
Sofya A. Kasatskaya ◽  
Vasiliy N. Zubov ◽  
Mark Izraelson ◽  
Tatiana O. Nakonechnaya ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Human Aging ◽  
Receptor Repertoire ◽  
Naïve T Cell ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire ◽  
Naive T Cell

Interleukin-7–treated naive T cells can be productively infected by T-cell–adapted and primary isolates of human immunodeficiency virus 1

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3310-3318 ◽  
Author(s):  
Carolyn M. Steffens ◽  
Elizabeth Z. Managlia ◽  
Alan Landay ◽  
Lena Al-Harthi
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Productive Infection ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Although human immunodeficiency virus (HIV)gag/pol DNA can be detected in naive T cells, whether naive T cells can be productively infected by HIV is still questionable. Given that interleukin-7 (IL-7) is a prospective therapeutic immunomodulator for the treatment of HIV, we evaluated the effect of IL-7 on promoting naive T-cell infection of laboratory-adapted (IIIB), M-tropic, and primary isolates of HIV. Initially, we determined that the 3 cell surface markers widely used to identify naive T cells (CD45RA+CD45RO−, CD45RA+CD62L+, and CD45RO−CD27+CD95low) are all equivalent in T-cell receptor excision circle content, a marker for the replicative history of a cell as well as for de novo T cells. We therefore used CD45RA+CD45RO− expression to define naive T cells in this study. We demonstrate that although untreated or IL-2–treated naive T cells are not productively infected by HIV, IL-7 pretreatment mediated the productive infection of laboratory-adapted, M-tropic, and primary isolates of HIV as determined by p24 core antigen production. This up-regulation was between 8- and 58-fold, depending on the HIV isolate used. IL-7 pretreatment of naive T cells also potently up-regulated surface expression of CXCR4 but not CCR5 and mediated the expansion of naive T cells without the acquisition of the primed CD45RO phenotype. Collectively, these data indicate that IL-7 augments naive T-cell susceptibility to HIV and that under the appropriate environmental milieu, naive T cells may be a source of HIV productive infection. This information needs to be considered in evaluating IL-7 as an immunomodulator for HIV-infected patients.

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 Frequencies of FoxP3+ naïve T cells are related to both viral load and naïve T cell proliferation responses in HIV disease

2011 ◽  
Vol 90 (3) ◽  
pp. 621-628 ◽  
Author(s):  
Benigno Rodriguez ◽  
Douglas A. Bazdar ◽  
Nicholas Funderburg ◽  
Robert Asaad ◽  
Angel A. Luciano ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
T Cell Proliferation ◽  
Hiv Disease ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naïve T Cell ◽  
Naive T Cell

scholarly journals Decreased Thymic Output Accounts for Decreased Naive T Cell Numbers in Children with Down Syndrome

2011 ◽  
Vol 186 (7) ◽  
pp. 4500-4507 ◽  
Author(s):  
Beatrijs L. P. Bloemers ◽  
Louis Bont ◽  
Roel A. de Weger ◽  
Sigrid A. Otto ◽  
Jose A. Borghans ◽  
...  
Keyword(s):  
Down Syndrome ◽  
T Cell ◽  
Children With Down Syndrome ◽  
Cell Numbers ◽  
Thymic Output ◽  
Naïve T Cell ◽  
Naive T Cell

scholarly journals Programmed death-1 (PD-1) defines a transient and dysfunctional oligoclonal T cell population in acute homeostatic proliferation

2007 ◽  
Vol 204 (10) ◽  
pp. 2321-2333 ◽  
Author(s):  
Sue-Jane Lin ◽  
Craig D. Peacock ◽  
Kapil Bahl ◽  
Raymond M. Welsh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Annexin V ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Homeostatic Proliferation ◽  
Programmed Death ◽  
Cell Fractions

The host responds to lymphopenic environments by acute homeostatic proliferation, which is a cytokine- and endogenous peptide-driven expansion of lymphocytes that restores the numbers and diversity of T cells. It is unknown how these homeostatically proliferating (HP) cells are ultimately controlled. Using a system where lymphocytic choriomeningitis virus–immune C57BL/6 splenocytes were transferred into lymphopenic T cell–deficient hosts and allowed to reconstitute the environment, we defined the following three populations of T cells: slowly dividing Ly6C+ cells, which contained bona fide virus-specific memory cells, and more rapidly dividing Ly6C− cells segregating into programmed death (PD)-1+ and PD-1− fractions. The PD-1+ HP cell population, which peaked in frequency at day 21, was dysfunctional in that it failed to produce interferon γ or tumor necrosis factor α on T cell receptor (TCR) stimulation, had down-regulated expression of interleukin (IL)-7Rα, IL-15Rβ, and Bcl-2, and reacted with Annexin V, which is indicative of a preapoptotic state. The PD-1+ HP cells, in contrast to other HP cell fractions, displayed highly skewed TCR repertoires, which is indicative of oligoclonal expansion; these skewed repertoires and the PD-1+ population disappeared by day 70 from the host, presumably because of apoptosis. These results suggest that PD-1 may play a negative regulatory role to control rapidly proliferating and potentially pathogenic autoreactive CD8+ T cells during homeostatic reconstitution of lymphopenic environments.

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