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.

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.

T-cell generation by lymph node resident progenitor cells

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 193-200 ◽  
Author(s):  
Rafik Terra ◽  
Isabelle Louis ◽  
Richard Le Blanc ◽  
Sophie Ouellet ◽  
Juan Carlos Zúñiga-Pflücker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Stromal Cells ◽  
Integration Site ◽  
T Cell Development ◽  
Cell Development ◽  
Lymphoid Organ ◽  
Oncostatin M ◽  
Cell Commitment

In the thymus, 2 types of Lin–Sca-1+ (lineage-negative stem cell antigen-1–positive) progenitors can generate T-lineage cells: c-Kithi interleukin-7 receptor α–negative (c-KithiIL-7Rα–) and c-KitloIL-7Rα+. While c-KithiIL-7Rα– progenitors are absent, c-KitloIL-7Rα+ progenitors are abundant in the lymph nodes (LNs). c-KitloIL-7Rα+ progenitors undergo abortive T-cell commitment in the LNs and become arrested in the G1 phase of the cell cycle because they fail both to up-regulate c-myb, c-myc, and cyclin D2 and to repress junB, p16INK4a, and p21Cip1/WAF. As a result, development of LN c-KitloIL-7Rα+ progenitors is blocked at an intermediate CD44+CD25lo development stage in vivo, and LN-derived progenitors fail to generate mature T cells when cultured with OP9-DL1 stromal cells. LN stroma can provide key signals for T-cell development including IL-7, Kit ligand, and Delta-like–1 but lacks Wnt4 and Wnt7b transcripts. LN c-KitloIL-7Rα+ progenitors are able to generate mature T cells when cultured with stromal cells producing wingless-related MMTV integration site 4 (Wnt4) or upon in vivo exposure to oncostatin M whose signaling pathway intersects with Wnt. Thus, supplying Wnt signals to c-KitloIL-7Rα+ progenitors may be sufficient to transform the LN into a primary T-lymphoid organ. These data provide unique insights into the essence of a primary T-lymphoid organ and into how a cryptic extrathymic T-cell development pathway can be amplified.

scholarly journals Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells

2001 ◽  
Vol 194 (1) ◽  
pp. 99-106 ◽  
Author(s):  
David Allman ◽  
Fredrick G. Karnell ◽  
Jennifer A. Punt ◽  
Sonia Bakkour ◽  
Lanwei Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Surface Proteins ◽  
Lineage Commitment ◽  
Double Positive ◽  
Hematopoietic Stem ◽  
Multipotent Progenitor Cells

Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4+CD8+ double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2−/−) or Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)−/− mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2−/− progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3ε and pre-Tα mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2−/− mice with a TCRβ transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell–specific signals associated with development of DP thymocytes.

Heme Metabolic Gene Expression In FLVCR-Knockout Mice During T Cell Development

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2787-2787
Author(s):  
Mary Philip ◽  
Alexandra R. Zaballa ◽  
Blake T. Hovde ◽  
Janis L. Abkowitz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Double Positive ◽  
Metabolic Gene Expression ◽  
Free Heme ◽  
Single Positive

Abstract Abstract 2787 Heme is essential for nearly every organism and cell. However, free heme can induce free radical formation and cellular damage, therefore cells must carefully regulate heme levels. The feline leukemia virus subgroup C receptor (FLVCR) exports heme from cells. Conditional deletion of Flvcr has been shown to cause progressive anemia in neonatal and adult mice (Science 319:825-8, 2008). Recently, we developed a transplant model in which developing lymphocytes lacked FLVCR while erythroid cells expressed FLVCR, preventing anemia, and found that CD4 and CD8 peripheral T cells were severely decreased while B cell numbers were normal. We further demonstrated that FLVCR-knockout thymocytes were blocked at the CD4CD8 double-positive (DP) stage (Blood [ASH Annual Meeting Abstracts] 114: 913, 2009). We hypothesized that developing T cells lacking FLVCR are arrested at the DP stage because of increased intracellular free heme (IFH). While heme is required for erythroid function, little is known about the role of heme in T cell development. Real-time dynamic quantification of IFH in vivo or from ex vivo tissue is a major challenge in heme biology. We reasoned that by measuring the expression of genes transcriptionally-regulated by heme, we could indirectly assess IFH. Three proteins are key regulators of IFH in non-erythroid cells: aminolevulinic acid synthase-1 (ALAS1) is the rate-limiting enzyme in heme synthesis, FLVCR exports heme, and heme oxygenase-1 (HMOX1) degrades heme. Normal thymic T cell development proceeds from the CD4CD8 double-negative (DN) to the CD4CD8 double-positive (DP) stage, which then go on to either the CD4 single-positive (CD4SP) or CD8 single-positive (CD8SP) stage. We flow-sorted cells from each stage and used multiplex quantitative PCR (qPCR) to determine that all three genes were expressed at higher levels early in normal T cell development during the DN and DP stages and then at lower levels in the CD4SP and CD8SP. Heme binding to the negative regulatory protein BACH1 causes dissociation of BACH1 from the Hmox1 promoter and increased Hmox1 transcription, while expression and stability of Alas1 mRNA is under negative feedback control by heme. Therefore, we predicted that increased IFH in FLVCR-knockout thymocytes would lead to an increase in Hmox1 mRNA and a decrease in Alas1 mRNA levels. We compared expression of heme metabolic genes in FLVCR-knockout and control thymocytes. Flvcr expression was nearly absent in FLVCR-knockout DN and DP cells, however, there was a slight increase in Flvcr expression by the few CD4SP and CD8SP present. To understand this result, we analyzed the extent of genomic Flvcr deletion in FLVCR-knockout thymocytes and peripheral B and T cells by genomic qPCR. DN and DP thymocytes had near complete deletion of Flvcr while CD4SP and CD8SP had slightly less-efficient deletion, likely accounting for the increased Flvcr mRNA levels. Strikingly, Flvcr deletion in the few peripheral T cells present was 50–60% in contrast to peripheral B cells (>90%): only those T cells with incomplete Flvcr deletion survived, further underscoring the absolute requirement for FLVCR in developing T cells. We next examined Hmox1 mRNA expression and found that Hmox1 expression was higher in FLVCR-knockout DP, CD4SP, and CD8SP compared to wild-type FLVCR controls. This supports our hypothesis that FLVCR loss leads to increased IFH during T cell development. Alas1 expression was similar in FLVCR-knockout and control thymocytes, a finding that could be explained because heme regulates ALAS1 activity not only at the transcriptional level but also at the post-transcriptional level. Thus Alas1 expression may not be a good indicator of IFH. In summary, we developed a method to quantify relative free heme levels in developing thymocytes through the measurement of heme metabolic gene expression and found that IFH levels were increased in FLVCR-knockout thymocytes compared to controls. Whether and how excess free heme derails the T cell developmental program, remains to be discovered. Disclosures: No relevant conflicts of interest to declare.

T-Cell Development Failure At β-Selection Checkpoint and TCRα/δ Locus Break Formation Associated with Chromosome 14 Translocation in Ataxia-Telangiectagia Mutated Deficient Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 184-184
Author(s):  
Takeshi Isoda ◽  
Masatoshi Takagi ◽  
Jinhua Piao ◽  
Shun Nakagama ◽  
Masaki Sato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Chromosome Break ◽  
Wild Type ◽  
Chromosome 14 ◽  
Hematopoietic Stem ◽  
T Cell Lymphopenia

Abstract Abstract 184FN2 Ataxia Telangiectagia (AT) is an autosomal recessive immunodeficiency, caused by mutation of ataxia telangiectagia mutated gene (ATM). ATM plays a crucial role for responding to DNA damages by extrinsic and intrinsic factors, and is a master regulator for maintaining DNA integrity. VDJ recombination and class switch recombination during lymphocyte maturation are the steps of intrinsic DNA damage response where ATM stabilizes DNA ends during recombination. ATM deficiency (ATM−/−) is known to predispose to T-cell lymphopenia and T-lineage lymphoma development. ATM−/− mouse has been shown to have a failure of T-cell development at the stage from double positive (DP) to single positive (SP) differentiation, which is due to a failure of T-cell receptor a (TCRa) recombination. Thymic lymphomas in ATM−/− mice have recently been shown to have a chromosome 14 translocation involving TCRd locus, suggesting that the first event for translocation arises during TCRd locus recombination at double negative (DN) stage. However, phenotypic features of T-cell development at DN phase and the timing of chromosome 14 translocation formation in ATM−/− are not fully elucidated. Here we demonstrate that T cells of ATM−/− mice show a failure at the transition from DN3a to DN3b at b and gd-selection checkpoints due to multiple TCR recombination failure in-vivo. Consistent with in-vivo developmental profiles of ATM−/− mice thymocytes, long term hematopoietic stem cells (LTR-HSCs) of ATM−/− mice cultured with OP9-DLL1 show a delay at b-selection checkpoint in chronological order. In this culture system, failures in gd-T-cell development are also observed in ATM−/− LTR-HSCs. Involvement of thymic stromas in the failure of this transition was ruled out by bone-marrow transplantation (BMT) of ATM−/− donor to WT recipient mice, where thymocytes reconstitution showed the same transition failure at b-selection checkpoint. Thymocytes in RAG2−/− mice are arrested at DN3 stage by a failure of cleavage of TCR genes, but the arrested thymocytes are known to progress to DP phase by anti-CD3e antibody stimulation. This experiment enables to analyze pre-TCR dependent differentiation signal machinery. Then anti-CD3e antibody was injected into RAG2−/−ATM−/− mouse and DN3 cells were shown to be led to DP phase, indicating that ATM itself is not involved in the differentiation program during DN to DP phase. These results suggested loss of ATM attenuates T cell differentiation at DN3a to DN3b transition due to inefficient TCRg, d and b locus recombination. Thus differentiation failure from DN3a to DN3b in ATM deficiency is presumably the primary cause of T cell lymphopenia at the stage prior to positive-selection. We next investigated when of the differentiation stages chromosome 14 translocation involving TCRa/d locus monitored. When the LTR-HSCs is cultured on the OP9-DLL1 cells with high-dose cytokine including 10 ng/ml of Flt3-L, IL-7 and SCF, differentiation of LTR-HSCs to T cells halt at DN2-3a phase before b-selection. Then, by reducing the Flt3-L and IL7 to 5 ng/ml and 1 ng/ml, respectively, the differentiation arrest is released and Tcell differentiation progresses from DN3a to DN3b. No detectable chromosome break at TCRad locus was observed at DN2-3a in wild type, while 5% of ATM−/− cells carried TCRad break, associated with chromosome 14 translocation in approximately 0.8 % of DN2-3a cells. After progression to DN3b-4 phase, TCRad locus break was still observed in AT cells at the frequency of 1%, and chromosome 14 translocations involving TCRad locus was observed in 12% of ATM−/− cells, which was in contrast to none in wild type cell. Mono- or bi-allelic TCRa/d breaks, chromosome 14 dicentric, and t (12:14) were also observed in minor population of ATM−/− cells. These results suggest that critical point for generation of chromosome 14 translocations involving TCRa/d locus lies at DN2-3a to 3b stages corresponding during b and gd selection checkpoint in ATM deficient thymocytes. Our findings revealed that developmental failure of T-cells in AT arises during b and gd–selection checkpoint, which leads to the breaks of TCRa/d locus and subsequent chromosome 14 translocation formation. Thus we propose T-lymphopenia and predisposition to T cell leukemia/lymphoma are tightly connected in ATM deficient condition. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals GARP–TGF-β Complexes Negatively Regulate Regulatory T Cell Development and Maintenance of Peripheral CD4+ T Cells In Vivo

2013 ◽  
Vol 190 (10) ◽  
pp. 5057-5064 ◽  
Author(s):  
Angela X. Zhou ◽  
Lina Kozhaya ◽  
Hodaka Fujii ◽  
Derya Unutmaz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cd4 T Cells ◽  
T Cell Development ◽  
Cell Development

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.

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.

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