scholarly journals CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation.

1996 ◽  
Vol 183 (4) ◽  
pp. 1707-1718 ◽  
Author(s):  
K F Byth ◽  
L A Conroy ◽  
S Howlett ◽  
A J Smith ◽  
J May ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cross Linking ◽  
Thymocyte Development ◽  
Double Positive

The CD45 transmembrane glycoprotein has been shown to be a protein phosphotyrosine phosphatase and to be important in signal transduction in T and B lymphocytes. We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45. The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls. The increase in B cell numbers is due to the specific expansion of two B cell subpopulations that express high levels of immunoglobulin (IgM) staining. T cell development is significantly inhibited in CD45-null animals at two distinct stages. The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both positive and negative selection require signals through the TCR complex, these findings suggest that CD45 is an important regulator of signal transduction via the TCR complex at multiple stages of T cell development. CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals. The proliferation of B cells in response to CD38 cross-linking is significantly reduced but not abolished by the CD45-null mutation. We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells.

Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury

2018 ◽  
Vol 46 (4) ◽  
pp. 441-449
Author(s):  
Sowmya Angusamy ◽  
Tamer Mansour ◽  
Mohammed Abdulmageed ◽  
Rachel Han ◽  
Brian C. Schutte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
T Cell Development ◽  
Adaptive Immune System ◽  
Cell Development ◽  
Thymocyte Development ◽  
Double Positive ◽  
Neonatal Mice ◽  
Single Positive

Abstract Background: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. Methods: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. Results: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. Conclusions: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

scholarly journals Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas

2015 ◽  
Vol 112 (25) ◽  
pp. 7773-7778 ◽  
Author(s):  
Hyung-Ok Lee ◽  
Xiao He ◽  
Jayati Mookerjee-Basu ◽  
Dai Zhongping ◽  
Xiang Hua ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Human T Cell

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell–specific ThPOK transgene (ThPOKconst mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOKconst RAG-deficient mice, which promotes development to the CD4+8+ (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

Critical and Complementary Role of FLT3 and Interleukin 7-Receptor Alpha Signaling in T Lymphocyte Development.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 112-112 ◽  
Author(s):  
Natalija Buza-Vidas ◽  
Henrik Ahlenius ◽  
Corrado M. Cilio ◽  
Marcus Svensson ◽  
William Agace ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Tyrosine Kinase Receptor ◽  
Thymocyte Development ◽  
Interleukin 7 ◽  
Cell Genesis ◽  
Cell Commitment ◽  
Deficient Mice

Abstract We recently demonstrated that signaling through the cytokine tyrosine kinase receptor flt3 and interleukin-7 receptor a (IL-7Ra) is indispensable for fetal and adult B cell commitment and development (Sitnicka et al., J. Exp. Med. 198: 1495, 2003). These receptors are also implicated to be important in regulation of T cell development, but their potential interdependence remains unexplored. We recently showed that flt3 ligand (FL)-deficient mice have reduced levels of early thymic progenitors as well as the common lymphoid progenitor (CLP) (Sitnicka et al., Immunity, 17:463, 2002). In the present study we investigated T cell development in mice deficient in FL and IL-7Ra expression. Strikingly, when compared to FL−/− and IL-7Ra−/− mice, FL−/−xIL-7Ra−/− (double deficient) mice (8-10 week old) lack visible lymph nodes and Peyer’s Patches. Thymic cellularity was dramatically reduced to only 0.3% of FL−/− and wild type (WT) controls and to only 4% of IL-7Ra−/− mice. In agreement with previous studies, IL-7Ra−/− thymocytes revealed a partial block at the progression from the DN2 (CD4−CD8−CD44+CD25+) to DN3 (CD4−CD8−CD44−CD25+) stage, while in FL−/−xIL-7Ra−/− mice DN1 (CD4−CD8−CD44+CD25−), DN2 and DN3 thymic progenitors were undetectable. Thus, severe reductions in early thymocyte development in FL−/−xIL-7Ra−/− mice support a similar role for cross talk between these two signaling pathways in T cell development as recently demonstrated for B cell genesis.

Notch Activation Converts B Cells into a T Cell Fate at the Earliest Stages of B Cell Committed Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3151-3151
Author(s):  
Jalal Taneera ◽  
Emma Smith ◽  
Mikael Sigvardsson ◽  
Emil Hansson ◽  
Urban Lindahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Stage ◽  
Cell Commitment ◽  
Notch Activation

Abstract Notch activation has been suggested to promote T cell development at the expense of B cell commitment at the level of a common lymphoid progenitor prior to B cell commitment. Here, we explored the possibility that Notch activation might be able to switch the fate of already committed B cell progenitors towards T cell development upon Notch activation. To address this we overexpressed constitutively activated Notch-3 (N3IC) in B cell progenitors purified from transgenic mice in which human CD25 is expressed under control of the λ5 promoter. Strikingly, whereas untransduced and control transduced B220+λ5+CD3− B cell progenitors gave rise exclusively to B cells, CD4+ and CD8+ T cells but no B cells were derived from N3IC-transduced cells when transplanted into sublethally irradiated NOD-SCID mice. Gene expression profiling demonstrated that untransduced B220+ λ5+CD3− B cell progenitors expressed λ5 and CD19 but not the T cell specific genes GATA-3, lck and pTα, whereas CD3+ T cells derived from N3IC-transduced B220+λ5+CD3−cells failed to express λ5 and CD19, but were positive for GATA-3, lck and pTα expression as well as a and b T cell rearrangement. Furthermore, DJ rearrangements were detected at very low levels in CD3+ cells isolated from normal non-transduced BM, but were more abundant in the N3IC-transduced CD3+ BM cells. Noteworthy, N3IC-transduced B220+λ5+CD3−CD19+ proB cell progenitors failed to generate B as well as T cells, whereas N3IC-transduced B220+λ5+CD3−CD19− pre-proB cells produced exclusively T cells, even when evaluated at low cell numbers. In conclusion Notch activation can switch committed B cell progenitors from a B cell to a T cell fate, but this plasticity is lost at the Pro-B cell stage, upon upregulation of CD19 expression.

T and B cell development in pituitary deficient insulin-like growth factor-II transgenic dwarf mice

1997 ◽  
Vol 155 (1) ◽  
pp. 165-170 ◽  
Author(s):  
R Kooijman ◽  
SC van Buul-Offers ◽  
LE Scholtens ◽  
RG Reijnen-Gresnigt ◽  
BJ Zegers
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Igf I ◽  
Dwarf Mice

Treatment of mice with IGF-I stimulates T and B cell development. We showed that overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell development. In the present study, we further addressed the in vivo effects of IGF-II in the absence of IGF-I to get more insight into the potential abilities of IGF-II to influence T and B cell development. To this end, we studied lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin, GH and thyroid-stimulating hormone deficient and as a consequence show low serum IGF-I levels. We showed that T cell development was stimulated to the same extent as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of nucleated bone marrow cells and the number of immature B cells without having an effect on the number of mature B cells in spleen and bone marrow. Our data show that IGF-II has preferential effects on T cell development compared with B development, and that these preferential effects also occur in the absence of measurable IGF-I levels.

T-cell developmental blockage by tachykinin antagonists and the role of hemokinin 1 in T lymphopoiesis

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2165-2172 ◽  
Author(s):  
Yu Zhang ◽  
Christopher J. Paige
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Double Positive ◽  
Peptide Family ◽  
Tachykinin Antagonists ◽  
B Cell Precursors

Abstract Hemokinin 1 (HK-1) is a new member of the tachykinin peptide family that is expressed in hematopoietic cells. Recent reports studying mouse, rat, and human orthologs of HK-1 demonstrate a broader distribution than originally reported. Our previous studies demonstrated that HK-1, by promoting proliferation, survival, and possibly maturation of B-cell precursors, plays an important role in B lymphopoiesis. Here we present data showing that HK-1 also influences T-cell development at a similar stage of differentiation. This peptide enhanced the proliferation of T-cell precursors and increased the number of thymocytes in fetal thymus organ cultures (FTOCs). Tachykinin antagonists, on the other hand, greatly reduced the cellularity of thymi both in vivo and in vitro. The major reduction occurred in the CD4/CD8 double-positive (DP) cells and the CD44–CD25+ subset of the CD4/CD8 double-negative (DN) cells. Of note, these populations also express HK-1, raising the possibility of autocrine or paracrine pathways influencing T-cell development as we previously reported for B-cell development. Consistent with this, the detrimental effect of tachykinin antagonists could be partially overcome with exogenous HK-1 peptide.

Overlapping functions of human CD3δ and mouse CD3γ in αβ T-cell development revealed in a humanized CD3γ-deficient mouse

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3420-3427 ◽  
Author(s):  
Edgar Fernández-Malavé ◽  
Ninghai Wang ◽  
Manuel Pulgar ◽  
Wolfgang W. A. Schamel ◽  
Balbino Alarcón ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Double Negative ◽  
Wild Type ◽  
Thymocyte Development ◽  
Double Positive ◽  
Deficient Mice ◽  
Αβ T Cells

Abstract Humans lacking the CD3γ subunit of the pre-TCR and TCR complexes exhibit a mild αβ T lymphopenia, but have normal T cells. By contrast, CD3γ-deficient mice are almost devoid of mature αβ T cells due to an early block of intrathymic development at the CD4–CD8– double-negative (DN) stage. This suggests that in humans but not in mice, the highly related CD3δ chain replaces CD3γ during αβ T-cell development. To determine whether human CD3δ (hCD3δ) functions in a similar manner in the mouse in the absence of CD3γ, we introduced an hCD3δ transgene in mice that were deficient for both CD3δ and CD3γ, in which thymocyte development is completely arrested at the DN stage. Expression of hCD3δ efficiently supported pre-TCR–mediated progression from the DN to the CD4+CD8+ double-positive (DP) stage. However, αβTCR-mediated positive and negative thymocyte selection was less efficient than in wild-type mice, which correlated with a marked attenuation of TCR-mediated signaling. Of note, murine CD3γ-deficient TCR complexes that had incorporated hCD3δ displayed abnormalities in structural stability resembling those of T cells from CD3γ-deficient humans. Taken together, these data demonstrate that CD3δ and CD3γ play a different role in humans and mice in pre-TCR and TCR function during αβ T-cell development.

BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 3947-3953 ◽  
Author(s):  
Peter T. Tsai ◽  
Robert A. Lee ◽  
Hong Wu
Keyword(s):  
T Cell ◽  
Bone Morphogenetic Proteins ◽  
T Cell Development ◽  
Cell Development ◽  
Dependent Manner ◽  
Double Negative ◽  
Thymocyte Development ◽  
Double Positive ◽  
Stromal Compartment ◽  
Thymic Stroma

Abstract Thymocyte development is a non–cell-autonomous process that requires signals provided by the thymic stroma. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) derived from thymic stroma have been implicated as possible regulators of T-cell development. Using thymic organ culture, this study demonstrates that both BMP4 and FGF7/FGF10 arrest early T-cell development at the CD4-CD8-CD44+CD25- (double-negative 1 [DN1]) population and at the CD4-CD8- double-negative (DN) to CD4+CD8+ double-positive (DP) transition in a stromal compartment–dependent manner. Furthermore, BMP4 functions upstream of FGF7/FGF10, as the effects of BMP can be suppressed by cotreatment with an FGF receptor antagonist. BMP4 also acts directly on the thymic stroma to up-regulate the stroma-specific transcription factor Foxn1 and stroma-expressed chemokines. Taken together, the data in this report demonstrate that BMP acts upstream of FGF in the regulation of early T-cell development and that BMP4 acts primarily through the thymic stroma, thereby altering the thymic microenvironment and affecting thymopoiesis.

scholarly journals Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice.

1993 ◽  
Vol 177 (2) ◽  
pp. 305-316 ◽  
Author(s):  
B E Rich ◽  
J Campos-Torres ◽  
R I Tepper ◽  
R W Moreadith ◽  
P Leder
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
T Cell Development ◽  
Living Organism ◽  
Cell Development ◽  
Lymphoid Tissues ◽  
Double Positive ◽  
Interleukin 7 ◽  
T Cell Lymphomas ◽  
Skin Homing

To investigate the role of interleukin 7 (IL-7) in the development of the lymphoid system, we have generated two lines of transgenic mice carrying an IL-7 cDNA fused to an immunoglobulin heavy chain promoter and enhancer. This transgene is expressed in the bone marrow, lymph nodes, spleen, thymus, and skin provoking a perturbation of T cell development characterized by a marked reduction of CD4+ CD8+ (double-positive) thymocytes. Quite unexpectedly, however, both lines also develop a progressive cutaneous disorder involving a dermal lymphoid infiltrate that results in progressive alopecia, hyperkeratosis, and exfoliation. Although the infiltrate is primarily composed of T lineage cells, its development is not impeded in the athymic nu/nu background. Furthermore, the phenotype can be transmitted horizontally by transplanting lymphoid tissues or skin to syngeneic wild-type mice. Thus, the phenotype is conveyed by skin-homing, mobile cells (presumably the infiltrating lymphocytes) in a cell-autonomous fashion. In addition to the skin phenotype, this transgene also provokes the development of a lymphoproliferative disorder that induces B and T cell lymphomas within the first 4 mo of life. These findings suggest potential physiologic actions of IL-7 in T cell development and in cutaneous immunity. They also demonstrate that IL-7 can act as an oncogene in the living organism.

scholarly journals Transgenic Expression of a Mutant Ribonuclease Regnase-1 in T Cells Disturbs T Cell Development and Functions

2021 ◽  
Vol 12 ◽  
Author(s):  
Gangcheng Kong ◽  
Yaling Dou ◽  
Xiang Xiao ◽  
Yixuan Wang ◽  
Yingzi Ming ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Rna Binding ◽  
T Cell Development ◽  
Cell Development ◽  
Double Positive ◽  
Transgenic Expression ◽  
Spleen And Lymph Nodes

Regnase-1 is an RNA-binding protein with ribonuclease activities, and once induced it controls diverse immune responses by degrading mRNAs that encode inflammatory cytokines and costimulatory molecules, thus exerting potent anti-inflammatory functions. However, Regnase-1 is extremely sensitive to degradation by proteases and therefore short-lived. Here, we constructed a mutant Regnase-1 that is resistant to degradation and expressed this mutant in vivo as a transgene specifically in T cells. We found that the mutant Regnase-1 transgenic mice exhibited profound lymphopenia in the periphery despite grossly normal spleen and lymph nodes, and spontaneously accepted skin allografts without any treatment. Mechanistic studies showed that in the transgenic mice thymic T cell development was disrupted, such that most of the developing thymocytes were arrested at the double positive stage, with few mature CD4+ and CD8+ T cells in the thymus and periphery. Our findings suggest that interfering with the dynamic Regnase-1 expression in T cells disrupts T cell development and functions and further studies are warranted to uncover the mechanisms involved.

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