scholarly journals Asynchronous Coreceptor Downregulation after Positive Thymic Selection: Prolonged Maintenance of the Double Positive State in CD8 Lineage Differentiation Due to Sustained Biosynthesis of the CD4 Coreceptor

1997 ◽  
Vol 185 (2) ◽  
pp. 357-362 ◽  
Author(s):  
Thomas Barthlott ◽  
Hubertus Kohler ◽  
Klaus Eichmann
Keyword(s):  
T Cell ◽  
Degradation Kinetics ◽  
Cell Lineage ◽  
Turnover Rates ◽  
Double Positive ◽  
Color Flow ◽  
Temporal Asymmetry ◽  
Translational Activity ◽  
Lineage Differentiation

In several experimental systems analyzing the generation of single positive (SP) thymocytes from double positive (DP) thymocytes, CD4 SP cells have been shown to appear before CD8 SP cells. This apparent temporal asymmetry in the maturation of CD4 SP and CD8 SP thymocytes could either be due to divergent molecular differentiation programs of the two T cell lineages, or merely to slower degradation kinetics of the CD4 protein. To study this question in unmanipulated in vivo differentiation, we developed a four-color flow cytometry protocol which identifies a recently activated TCRintCD69pos thymocyte population containing DP cells and early CD4 SP cells but no CD8 SP cells. We show that these TCRintCD69pos thymocytes represent a transitory stage in the mainstream αβ T cell lineage. The precursors of the CD8 SP cells are contained in this population as incompletely selected DP cells. Moreover, we show that expression of both coreceptors in the TCRintCD69pos population depends on transcriptional and translational activity, thus excluding differences in turnover rates of the CD4 and CD8 proteins as the cause of the asynchrony in differentiation of the CD4 and CD8 lineages.

scholarly journals Stages versus subsets: Invariant Natural Killer T cell lineage differentiation

Cytokine ◽  
2015 ◽  
Vol 72 (2) ◽  
pp. 204-209 ◽  
Author(s):  
Heather M. Buechel ◽  
Martin H. Stradner ◽  
Louise M. D’Cruz
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Cell Lineage ◽  
Natural Killer T Cell ◽  
Lineage Differentiation ◽  
Invariant Natural Killer ◽  
Killer T Cell ◽  
Natural Killer T

Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4342-4346 ◽  
Author(s):  
Claudiu V. Cotta ◽  
Zheng Zhang ◽  
Hyung-Gyoon Kim ◽  
Christopher A. Klug
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Nk Cell ◽  
Cell Lineage ◽  
Blood Analysis ◽  
Hematopoietic Stem ◽  
Peripheral Blood Analysis

Abstract Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.

scholarly journals T-cell lineage commitment and cytokine responses of thymic progenitors

Blood ◽  
1995 ◽  
Vol 86 (5) ◽  
pp. 1850-1860 ◽  
Author(s):  
TA Moore ◽  
A Zlotnik
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cultured Cells ◽  
Critical Role ◽  
Cell Lineage ◽  
Lineage Commitment ◽  
Organ Cultures ◽  
Cell Commitment

The earliest steps of intrathymic differentiation recently have been elucidated. It has been reported that both CD4lo (CD44+ CD25- c-kit+ CD3- CD4lo CD8-) and pro-T cells (CD44+ CD25+ c-kit+ CD3- CD4- CD8-, representing the next step in maturation) exhibit germline T-cell receptor beta and gamma loci, suggesting that neither population is exclusively committed to the T-cell lineage. Several groups have shown that CD4lo cells retain the capacity to generate multiple lymphoid lineages in vivo; however, the lineage commitment status of pro-T cells is unknown. To determine when T-cell lineage commitment occurs, we examined the ability of sorted CD4lo and pro-T cells to generate lymphoid lineage cells in vivo or in fetal thymic organ cultures (FTOCs). When intravenously injected into scid mice, CD4lo cells generated both T and B cells, whereas the progeny of pro-T cells contained T cells exclusively. Fetal thymic organ cultures repopulated with CD4lo cells contained both T and natural killer (NK) cells, whereas cultures repopulated with pro-T cells contained T cells almost exclusively. These observations strongly suggest that T-cell lineage commitment occurs during the transition of CD4lo to pro-T cells. Because it is likely that the thymic microenvironment plays a critical role in T-cell commitment, we compared the responses of CD4lo and pro-T cells to various cytokine combinations in vitro, as well as the ability of the cultured cells to repopulate organ cultures. Cytokine combinations that maintained T-cell repopulation potential for both CD4lo and pro-T cells were found. CD4lo cells proliferated best in response to the combination containing interleukin-1 (IL-1), IL-3, IL- 6, IL-7, and stem cell factor (SCF). Unlike CD4lo cells, pro-T cells were much more dependent upon IL-7 for proliferation and FTOC repopulation. However, combinations of cytokines lacking IL-7 were found that maintained the T-cell repopulating potential of pro-T cells, suggesting that, whereas this cytokine is clearly very important for normal pro-T cell function, it is not an absolute necessity during early T-cell expansion and differentiation.

scholarly journals A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity

2019 ◽  
Vol 30 (8) ◽  
pp. 1439-1453 ◽  
Author(s):  
Julia Hagenstein ◽  
Simon Melderis ◽  
Anna Nosko ◽  
Matthias T. Warkotsch ◽  
Johannes V. Richter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Th17 Cells ◽  
Inflammatory Diseases ◽  
Double Positive ◽  
T Effector Cells ◽  
Suppressive Capacity

BackgroundNew therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown.MethodsTo learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell–specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations.ResultsLack of IL-6Ra signaling in mouse CD4+ T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORγt+Foxp3+ double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra−/− Tregs resulted in severe aggravation of GN in mice.ConclusionsOur data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell–intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt+ biTregs. These results advocate caution and indicate that IL-6–directed therapies for GN need to be cell-type specific.

β-Selection Is Associated With the Onset of CD8β Chain Expression on CD4+CD8+ Pre-T Cells During Human Intrathymic Development

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3491-3498 ◽  
Author(s):  
Yolanda R. Carrasco ◽  
César Trigueros ◽  
Almudena R. Ramiro ◽  
Virginia G. de Yébenes ◽  
Marı́a L. Toribio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Control Point ◽  
Intermediate Stage ◽  
Cell Receptor ◽  
Resting Cells ◽  
Double Positive ◽  
Human T Cell ◽  
A Minor

T-cell precursors that undergo productive rearrangements at the T-cell receptor (TCR) β locus are selected for proliferation and further maturation, before TCR expression, by signaling through a pre–TCR composed of the TCRβ chain paired with a pre–TCR (pT) chain. Such a critical developmental checkpoint, known as β-selection, results in progression from CD4−CD8− double negative (DN) to CD4+CD8+ double positive (DP) TCRβ−thymocytes. In contrast to mice, progression to the DP compartment occurs in humans via a CD4+ CD8−intermediate stage. Here we show that the CD4+CD8− to CD4+ CD8+ transition involves the sequential acquisition of the  and β chains of CD8 at distinct maturation stages. Our results indicate that CD8, but not CD8β, is expressed in vivo in a minor subset of DP TCRβ− thymocytes, referred to as CD4+CD8+ pre-T cells, mostly composed of resting cells lacking cytoplasmic TCRβ chain (TCRβic). In contrast, expression of CD8β heterodimers was selectively found on DP TCRβ− thymocytes that express TCRβicand are enriched for cycling cells. Interestingly, CD4+CD8+ pre-T cells are shown to be functional intermediates between CD4+ CD8−TCRβic− and CD4+CD8β+ TCRβic+thymocytes. More importantly, evidence is provided that onset of CD8β and TCRβic expression are coincident developmental events associated with acquisition of CD3 and pT chain on the cell surface. Therefore, we propose that the CD4+CD8+ to CD4+CD8β+ transition marks the key control point of pre-TCR–mediated β-selection in human T-cell development.

scholarly journals In vivo and in vitro clonal deletion of double-positive thymocytes.

1992 ◽  
Vol 175 (5) ◽  
pp. 1307-1316 ◽  
Author(s):  
N J Vasquez ◽  
J Kaye ◽  
S M Hedrick
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytochrome C ◽  
Cyclosporin A ◽  
Negative Selection ◽  
Double Positive ◽  
Antigen Dose ◽  
Mhc Molecules

To study the processes of thymic development, we have established transgenic mice expressing and alpha/beta T cell antigen receptor (TCR) specific for cytochrome c associated with class II major histocompatibility complex (MHC) molecules. The transgenic TCR chains are expressed by most of the thymocytes in these mice, and these cells have been shown to efficiently mature in association with Ek- and Ab-encoded class II MHC molecules. This report describes a characterization of the negative selection of these transgenic thymocytes in vivo that is associated with the expression of As molecules. Negative selection by As molecules appears to result in the deletion of a late stage of CD4/CD8 double-positive thymocytes in that there is a virtual absence of transgenic TCR bearing CD4 single-positive thymocytes. This phenotype is accompanied by the appearance of CD4/CD8 double-negative thymocytes and peripheral T cells that are functionally antigen reactive. The process of negative selection has also been investigated using an in vitro culture system. Upon presentation of cytochrome c by Eb-expressing nonthymic antigen-presenting cells, there occurs an antigen dose-dependent deletion of the majority of CD4/CD8 double-positive thymocytes. In contrast, presentation of Staphylococcal enterotoxin A by Eb in vitro results in minimal deletion of double-positive thymocytes. In addition, we use this in vitro model to examine the effects of cyclosporin A on negative selection. In contrast to its effects on mature T cells, and the findings of others in vivo, cyclosporin A does not inhibit antigen-induced deletion of double-positive thymocytes. Finally, a comparison of the antigen dose responses for thymocyte deletion and for peripheral T cell activation indicates that double-positive thymocyte recognition is more sensitive than mature T cells to antigen recognition.

scholarly journals Multiple extrathymic precursors contribute to T-cell development with different kinetics

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1137-1144 ◽  
Author(s):  
Namita Saran ◽  
Marcin Łyszkiewicz ◽  
Jens Pommerencke ◽  
Katrin Witzlau ◽  
Ramin Vakilzadeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Precursor ◽  
Lineage Differentiation ◽  
Multipotent Cells ◽  
Kinetics Of

Abstract T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches.

Cytokine-induced IL-10–secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4475-4483 ◽  
Author(s):  
Alistair Noble ◽  
Angela Giorgini ◽  
Jamie A. Leggat
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Lineage ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Cell Interaction ◽  
Cell Contact ◽  
Cell Based Therapy

Abstract Populations of regulatory T cells (Tregs) control autoimmune and allergic immunopathology induced by self or foreign antigens. Several types of CD4+ MHC class II–restricted Treg populations have been characterized, but the biology of CD8+, MHC class I–restricted Tregs is less understood. We show here that CD8+ Tregs are rapidly generated in the presence of IL-4 and IL-12, produce IL-10, and exhibit a unique cell-surface phenotype with coexpression of activation and naive cell-associated markers. They block activation of naive or effector T cells and suppress IgG/IgE antibody responses and graft-versus-host disease in vivo. Suppression is dependent on cell contact and mediated by direct T-cell–T-cell interaction that antagonizes T-cell–receptor (TCR) signals. The data establish the existence of a CD8 T-cell suppressor effector subset distinct in both phenotype and function from T cytotoxic 1 (Tc1) and Tc2 cells. Production of such CD8 Tregs has potential for cell-based therapy of CD4 or CD8 T-cell–mediated disease.

scholarly journals Targeting ion channel TRPM7 promotes thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation

2018 ◽  
Author(s):  
Suresh K. Mendu ◽  
Michael S. Schappe ◽  
Emily K. Moser ◽  
Julia K. Krupa ◽  
Jason S. Rogers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Ion Channel ◽  
Cell Lineage ◽  
Foxp3 Expression ◽  
List Type ◽  
Thymic Development ◽  
Genetic Deletion

In BriefGenetic deletion of Trpm7 in T-cells or pharmacological inhibition of TRPM7 channel promotes the development of fully functional Treg cells by increasing IL-2Rα and STAT5-dependent FOXP3 expression in the developing thymocytes. The study identifies the ion channel TRPM7 as a putative drug target to increase Treg numbers in vivo and induce immunotolerance.HIGHLIGHTSIon channel TRPM7 controls Treg developmentThe deletion of Trpm7 in the T-cell lineage increases fully functional Treg cells in the peripheryTRPM7 negatively regulates Foxp3 expression by restraining IL-2-dependent STAT5 activationInhibition of TRPM7 channel by FTY720 promotes the development of functional Treg cellsSUMMARYThe thymic development of regulatory T cells (Treg), the crucial suppressors of the effector T cells (Teff), is governed by the transcription factor FOXP3. Despite the clinical significance of Treg cells, there is a dearth of druggable molecular targets capable of increasing Treg numbers in vivo. We report a surprising discovery that TRPM7 restrains Treg development by negatively regulating STAT5-dependent Foxp3 expression. The deletion of Trpm7 potentiates the thymic development of Treg cells, leads to a significantly higher frequency of functional Treg cells in the periphery and renders the mice highly resistant to T cell-dependent hepatitis. The deletion of Trpm7 or the inhibition of TRPM7 channel activity by the FDA-approved prodrug FTY720, increases IL-2 sensitivity through a feed forward positive feedback loop involving high IL-2Rα expression and STAT5 activation. Enhanced IL-2 signaling increases the expression of Foxp3 in thymocytes and promotes the development of Treg cells. Thus, TRPM7 emerges as the first ion channel that can be drugged to increase Treg numbers, revealing a novel pharmacological path toward the induction of immune tolerance.

scholarly journals CD4+ CD8αα+ T Cells in the Gastric epithelium Mediate Chronic Inflammation Induced by Helicobacter Felis

2021 ◽  
Author(s):  
Guojing Ruan ◽  
An Huang ◽  
Chupeng Hu ◽  
Ningyin Xu ◽  
Menghui Fan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Efficacy ◽  
Gastric Epithelium ◽  
Double Positive ◽  
Helicobacter Felis ◽  
Local Immunosuppression ◽  
Infiltrating Lymphocytes

Abstract CD4+ CD8αα+ double-positive intraepithelial T lymphocytes (DP T cells), a newly characterized subset of intraepithelial T cell, has been reported to contribute to local immunosuppression. However, whether DP T cells are present in Helicobacter. pylori-induced gastritis, and their relationship with disease prognosis remain to be elucidated. In this study, We established chronic gastritis models through Helicobacter felis (H. felis) infection. Gastric infiltrating lymphocytes were isolated from H. felis-induced gastritis mice and analyzed by flow cytometry. Our results suggest that DP T cells frequency in H. felis-induced gastritis mice was higher than the uninfected mice. Gastric DP T cells derived from lamina propria cells, which distributed in the gastric epithelial layer. We found that DP T cells exhibited anti-inflammatory function. In vitro, DP T cells inhibited the maturation of dendritic cells and the proliferation of CD4+ T cell. The elimination of CD4+CD8αα+ T cells in vivo resulted in severe gastritis and a reduction of H. felis load. Additionally, vaccine with silk fibroin as delivery systems enhanced vaccine efficacy by reducing DP T cells. We demonstrated that DP T cells performed an immunosuppressive role in Helicobacter felis-induced gastritis. These findings revealed that DP T cells may affect the prognosis of the disease and the vaccine efficacy.

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