The linkage between T-cell and dendritic cell development in the mouse thymus

ABSTRACT Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.

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C1q regulation of dendritic cell development: Distinct cytokine production and T cell stimulation

Molecular Immunology ◽

10.1016/j.molimm.2011.06.409 ◽

2011 ◽

Vol 48 (14) ◽

pp. 1725

Author(s):

J. Lu ◽

B.K. Teh ◽

J.G. Yeo ◽

M.C. Lai

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Cytokine Production ◽

Cell Development ◽

Cell Stimulation ◽

T Cell Stimulation

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Dll4–Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice

Journal of Experimental Medicine ◽

10.1084/jem.20111615 ◽

2012 ◽

Vol 209 (5) ◽

pp. 1011-1028 ◽

Cited By ~ 34

Author(s):

Fabienne Billiard ◽

Camille Lobry ◽

Guillaume Darrasse-Jèze ◽

Janelle Waite ◽

Xia Liu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

Notch Signaling ◽

Cell Fate ◽

Treg Cell ◽

De Novo ◽

Alternative Pathway ◽

Treg Cells ◽

Cell Development

Delta-like ligand 4 (Dll4)–Notch signaling is essential for T cell development and alternative thymic lineage decisions. How Dll4–Notch signaling affects pro-T cell fate and thymic dendritic cell (tDC) development is unknown. We found that Dll4 pharmacological blockade induces accumulation of tDCs and CD4+CD25+FoxP3+ regulatory T cells (Treg cells) in the thymic cortex. Both genetic inactivation models and anti-Dll4 antibody (Ab) treatment promote de novo natural Treg cell expansion by a DC-dependent mechanism that requires major histocompatibility complex II expression on DCs. Anti-Dll4 treatment converts CD4−CD8−c-kit+CD44+CD25− (DN1) T cell progenitors to immature DCs that induce ex vivo differentiation of naive CD4+ T cells into Treg cells. Induction of these tolerogenic DN1-derived tDCs and the ensuing expansion of Treg cells are Fms-like tyrosine kinase 3 (Flt3) independent, occur in the context of transcriptional up-regulation of PU.1, Irf-4, Irf-8, and CSF-1, genes critical for DC differentiation, and are abrogated in thymectomized mice. Anti-Dll4 treatment fully prevents type 1 diabetes (T1D) via a Treg cell–mediated mechanism and inhibits CD8+ T cell pancreatic islet infiltration. Furthermore, a single injection of anti-Dll4 Ab reverses established T1D. Disease remission and recurrence are correlated with increased Treg cell numbers in the pancreas-draining lymph nodes. These results identify Dll4–Notch as a novel Flt3-alternative pathway important for regulating tDC-mediated Treg cell homeostasis and autoimmunity.

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Tributyltin acetate-induced immunotoxicity is related to inhibition of T cell development in the mouse thymus

Molecular & Cellular Toxicology ◽

10.1007/s13273-015-0022-6 ◽

2015 ◽

Vol 11 (2) ◽

pp. 231-239 ◽

Cited By ~ 1

Author(s):

Eunji Im ◽

Heejeong Kim ◽

Jiye Kim ◽

Hyojin Lee ◽

Hyunwon Yang

Keyword(s):

T Cell ◽

T Cell Development ◽

Cell Development ◽

Mouse Thymus ◽

Tributyltin Acetate

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Immunofluorescent Localization of Non-myelinating Schwann Cells and Their Interactions With Immune Cells in Mouse Thymus

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155418778543 ◽

2018 ◽

Vol 66 (11) ◽

pp. 775-785 ◽

Cited By ~ 4

Author(s):

Dailun Hu ◽

Philip K. Nicholls ◽

Changfu Yin ◽

Khama Kelman ◽

Qionglan Yuan ◽

...

Keyword(s):

T Cell ◽

Schwann Cells ◽

Immune Cells ◽

T Cell Development ◽

Cell Development ◽

Nerve Fibers ◽

Endocrine Function ◽

Immunofluorescent Staining ◽

Parasympathetic Nerve ◽

Mouse Thymus

The thymus is innervated by sympathetic/parasympathetic nerve fibers from the peripheral nervous system (PNS), suggesting a neural regulation of thymic function including T-cell development. Despite some published studies, data on the innervation and nerve-immune interaction inside the thymus remain limited. In the present study, we used immunofluorescent staining of glial fibrillary acidic protein (GFAP) coupled with confocal microscopy/three-dimensional (3D) reconstruction to reveal the distribution of non-myelinating Schwann cells (NMSC) and their interactions with immune cells inside mouse thymus. Our results demonstrate (1) the presence of an extensive network of NMSC processes in all compartments of the thymus including the capsule, subcapsular region, cortex, cortico-medullary junction, and medulla; (2) close associations/interactions of NMSC processes with blood vessels, indicating the neural control of blood flow inside the thymus; (3) the close “synapse-like” association of NMSC processes with various subsets of dendritic cells (DC; e.g., B220+ DCs, CD4+ DCs, and CD8+ DCs), and lymphocytes (B cells, CD4+/CD8+ thymocytes). Our novel findings concerning the distribution of NMSCs and the associations of NMSCs and immune cells inside mouse thymus should help us understand the anatomical basis and the mechanisms through which the PNS affects T-cell development and thymic endocrine function in health and disease.

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T/B lineage choice occurs prior to intrathymic Notch signaling

Blood ◽

10.1182/blood-2004-12-4881 ◽

2005 ◽

Vol 106 (3) ◽

pp. 886-892 ◽

Cited By ~ 62

Author(s):

Benjamin C. Harman ◽

William E. Jenkinson ◽

Sonia M. Parnell ◽

Simona W. Rossi ◽

Eric J. Jenkinson ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Notch Signaling ◽

Fetal Liver ◽

T Cell Development ◽

Cell Lineage ◽

Cell Development ◽

Fetal Mouse ◽

Mouse Thymus ◽

B Lineage

Abstract Commitment of hemopoietic progenitors to the T-cell lineage is a crucial requirement for T-cell development, yet the timing and developmental cues regulating this process remain controversial. Here we have devised a technique to analyze the T-cell/B-cell lineage potential of precursors that have been recruited to the fetal mouse thymus but which have yet to contact the thymic epithelial microenvironment. We show that lymphoid progenitors arriving at the thymus are not bipotent T/B precursors, and provide evidence that intrathymic Notch signaling is not the mechanism determining T/B lineage choice in migrant precursors. Rather, we provide evidence that Notch signaling influences T/B lineage choice in lymphoid precursors through interactions with defined stromal components within the fetal liver. Collectively, our data redefine our understanding of the role and timing of Notch signaling in relation to lineage choices in lymphoid precursors.

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