scholarly journals The Src Family Tyrosine Kinase Fyn Regulates Natural Killer T Cell Development

1999 ◽  
Vol 190 (8) ◽  
pp. 1189-1196 ◽  
Author(s):  
Paul Gadue ◽  
Neil Morton ◽  
Paul L. Stein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Nk Cell ◽  
T Cell Development ◽  
Receptor Activation ◽  
Cell Development ◽  
T Cell Subsets ◽  
Nk T Cells ◽  
Nk T Cell

T lymphocytes express two Src tyrosine kinases, Lck and Fyn. While thymocyte and T cell subsets are largely normal in fyn−/− mice, animals lacking Lck have impaired T cell development. Here, it is shown that Fyn is required for the rapid burst of interleukin (IL)-4 and IL-13 synthesis, which occurs promptly after T cell receptor activation. The lack of cytokine induction in fyn mutant mice is due to a block in natural killer (NK) T cell development. Studies using bone marrow chimeras indicate that the defect behaves in a cell-autonomous manner, and the lack of NK T cells is probably not caused by inappropriate microenvironmental cues. Both NK T cells and conventional T cells express similar levels of Lck, implying that Fyn and Lck have distinct roles in regulating NK T cell ontogeny. The fyn mutation defines the first signaling molecule that is selectively required for NK T cell, but not for T lymphocyte or NK cell development.

scholarly journals A Critical Role for Natural Killer T Cells in Immunosurveillance of Methylcholanthrene-induced Sarcomas

2002 ◽  
Vol 196 (1) ◽  
pp. 119-127 ◽  
Author(s):  
Nadine Y. Crowe ◽  
Mark J. Smyth ◽  
Dale I. Godfrey
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Critical Role ◽  
Physiological Role ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Tumor Rejection ◽  
Nk T Cells ◽  
Nk T Cell

Natural killer (NK) T cells initiate potent antitumor responses when stimulated by exogenous factors such as interleukin (IL)-12 or α-galactosylceramide (α-GalCer), however, it is not clear whether this reflects a physiological role for these cells in tumor immunity. Through adoptive transfer of NK T cells from wild-type to NK T cell–deficient (T cell receptor [TCR] Jα281−/−) mice, we demonstrate a critical role for NK T cells in immunosurveillance of methylcholanthrene (MCA)-induced fibrosarcomas, in the absence of exogenous stimulatory factors. Using the same approach with gene-targeted and/or antibody-depleted donor or recipient mice, we have shown that this effect depends on CD1d recognition and requires the additional involvement of both NK and CD8+ T cells. Interferon-γ production by both NK T cells and downstream, non-NK T cells, is essential for protection, and perforin production by effector cells, but not NK T cells, is also critical. The protective mechanisms in this more physiologically relevant system are distinct from those associated with α-GalCer–induced, NK T cell–mediated, tumor rejection. This study demonstrates that, in addition to their importance in tumor immunotherapy induced by IL-12 or α-GalCer, NK T cells can play a critical role in tumor immunosurveillance, at least against MCA-induced sarcomas, in the absence of exogenous stimulation.

scholarly journals Observed Changes in Natural Killer and T cell Phenotypes with Evaluation of Immune Outcome in a Longitudinal Cohort Following Sofosbuvir-Based Therapy for Chronic Hepatitis C Infection

2019 ◽  
Vol 6 (6) ◽  
Author(s):  
Timothy J Stevenson ◽  
Youssef Barbour ◽  
Brian J McMahon ◽  
Lisa Townshend-Bulson ◽  
Annette M Hewitt ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis C ◽  
T Cell ◽  
Natural Killer ◽  
Chronic Hepatitis C ◽  
Nk Cell ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Immune Marker

Abstract Background Chronic hepatitis C virus (HCV) infection diminishes immune function through cell exhaustion and repertoire alteration. Direct acting antiviral (DAA)-based therapy can restore immune cell subset function and reduce exhaustion states. However, the extent of immune modulation following DAA-based therapy and the role that clinical and demographic factors play remain unknown. Methods We examined natural killer (NK) cell, CD4+, and CD8+ T cell subsets along with activation and exhaustion phenotypes across an observational study of sofosbuvir-based treatment for chronic HCV infection. Additionally, we examined the ability of clinical variables and duration of infection to predict 12 weeks of sustained virologic response (SVR12) immune marker outcomes. Results We show that sofosbuvir-based therapy restores NK cell subset distributions and reduces chronic activation by SVR12. Likewise, T cell subsets, including HCV-specific CD8+ T cells, show reductions in chronic exhaustion markers by SVR12. Immunosuppressive CD4+ regulatory T cells decrease at 4-weeks treatment and SVR12. We observe the magnitude and direction of change in immune marker values from pretreatment to SVR12 varies greatly among participants. Although we observed associations between the estimated date of infection, HCV diagnosis date, and extent of immune marker outcome at SVR12, our regression analyses did not indicate any factors as strong SVR12 outcome predictors. Conclusion Our study lends further evidence of immune changes following sofosbuvir-based therapy. Further investigation beyond SVR12 and into factors that may predict posttreatment outcome is warranted.

Identification of an NK/T cell–restricted progenitor in adult bone marrow contributing to bone marrow– and thymic-dependent NK cells

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 183-192 ◽  
Author(s):  
Hojjatollah Nozad Charoudeh ◽  
Yanjuan Tang ◽  
Min Cheng ◽  
Corrado M. Cilio ◽  
Sten Eirik W. Jacobsen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Potential ◽  
Close Link ◽  
Nk T Cell

Abstract Although bone marrow (BM) is the main site of natural killer (NK)–cell development in adult mice, recent studies have identified a distinct thymic-dependent NK pathway, implicating a possible close link between NK- and T-cell development in adult hematopoiesis. To investigate whether a potential NK-/T-lineage restriction of multipotent progenitors might take place already in the BM, we tested the full lineage potentials of NK-cell progenitors in adult BM. Notably, although Lin−CD122+NK1.1−DX5− NK-cell progenitors failed to commit to the B and myeloid lineages, they sustained a combined NK- and T-cell potential in vivo and in vitro at the single-cell level. Whereas T-cell development from NK/T progenitors is Notch-dependent, their contribution to thymic and BM NK cells remains Notch-independent. These findings demonstrate the existence of bipotent NK-/T-cell progenitors in adult BM.

scholarly journals The Effects of TLR Activation on T-Cell Development and Differentiation

2012 ◽  
Vol 2012 ◽  
pp. 1-32 ◽  
Author(s):  
Bo Jin ◽  
Tao Sun ◽  
Xiao-Hong Yu ◽  
Ying-Xiang Yang ◽  
Anthony E. T. Yeo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Development ◽  
Cell Receptor ◽  
Treg Cells ◽  
Cell Development ◽  
T Cell Subsets ◽  
Follicular Helper ◽  
Development And Differentiation

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

Mechanisms by Which NK T Cells Become the Predominant T Cell Subset in Mice after Irradiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4295-4295
Author(s):  
Zhenyu Yao ◽  
Yinping Liu ◽  
Jennifer McIntire ◽  
Samuel Strober
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Absolute Number ◽  
T Cell Subsets ◽  
Brdu Incorporation ◽  
T Cell Subset ◽  
Nk T Cells ◽  
The Absolute ◽  
Nk T Cell

Abstract Previously, we found that the percentage of NK T cells among all T cells in the spleen of mice treated with fractionated irradiation to the lymphoid tissues (Total lymphoid irradiation; TLI) with a total dose of 4,080 cGy increased markedly due to greater reduction in the absolute number of non-NK T cells as compared to NK T cells. The underlying mechanisms of the change in the T cell subsets after irradiation remained to be established. In the current study, C57BL/6 mice were given escalating single doses of 240, 1,000, 2,000 and 3,000 cGy total body irradiation (TBI). Splenocytes were harvested at 4 or 24 hours after irradiation, and the percentage and absolute number of NK T and non-NK T cells was determined. At the same time, the intracellular level of the anti-apoptotic protein, Bcl-2 was assayed by flow cytometry. In some studies, the turnover rate of NK T cells and non-NK T cells was examined by injection of BrdU and intracellular staining. At 4 hours after all doses of irradiation, neither the NK T nor non-NK T cell subset had a significant change in percentage or absolute number as compared to untreated controls. However, at 24 hours the percentage of NK T cells among all T cells had progressively increased with increased doses of TBI from 3% in the untreated controls to 65% in mice given 3,000 cGy. Whereas the absolute number of non-NK T cells decreased at least 1000 fold, the absolute number of NK T cells decreased approximately 50 fold after 3,000 cGy. The BrdU incorporation of NK T cells from irradiated mice was markedly reduced as compared to untreated mice, and was similar to that of non NK T cells in these irradiated mice. 8–12% of NK T cells and non NK T cells in untreated mice expressed a high level Bcl-2. As the dose of TBI increased progressively, the percentage of Bcl-2hi cells increased progressively to 89% amongst NK T cells and 70% amongst non-NK T cells. At each irradiation dose, the percentage of Bcl-2hi cells amongst NK T cells was higher than amongst non-NK T cells. There were 40×103 Bcl-2hi NK T cell and 10×103 Bcl-2hi non-NK T cells surviving per spleen at 24 hours after 3000 cGy TBI. The absolute number of Bcl-2hi NK T cells decreased by about two fold while the absolute number of Bcl-2hi non-NK T cells decreased by about 100 fold. These results indicate that the increased percentage of NK T cells amongst all T cells after irradiation is due to greater radioresistance rather than to more rapid replenishment of NK T cells as compared to non-NK T cells. We are investigating whether Bcl-2 plays a critical role in the extraordinary radioresistance of the NK T cells.

Notch Activation in Cord Blood Progenitors Induces a CD7+ Common NK/T Precursor Capable of NK Cell Commitment without Full Maturation and Differentiation of Lineage Committed Pre-T Lymphocytes with a Th1 Phenotype.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 644-644
Author(s):  
Veronika Bachanova ◽  
Valarie McCullar ◽  
Rosanna Wangen ◽  
Jeffrey S. Miller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Nk Cells ◽  
Nk Cell ◽  
T Cell Development ◽  
Notch Pathway ◽  
Cell Development ◽  
Dominant Negative ◽  
Cell Commitment

Abstract Activation of Notch signaling regulates differentiation and homeostasis of hematopoetic stem cells. After stimulation, intracellular Notch is proteolytically released and by binding the CSL complex and co-activator MAML, and initiates transcription of downstream genes. We hypothesize that Notch is important for distinct stages of lymphoid development. Human cord blood CD34+ progenitor cells were transduced with retrovirus based eGFP-control, eGFP-Notch and Notch Dominant Negative/MAML (eGFP-DN) constructs. CD34+/eGFP+ were sorted and then co-cultured with the mouse embryonic liver cell line EL08.1D2 and exogenous human cytokines (IL-3. IL-7, IL-15, Flt3 ligand and c-kit ligand). As early as 48 hours after transduction, CD34+/Notch+ cells gave rise to population of lymphoid precursors CD34+CD7+CD10- (42±5% of all cells) while essentially no cells with this phenotype were detected with the control or DN construct. Proliferation of eGFP-Notch transduced cells in a 6-day thymidine incorporation assay was higher compared to eGFP-DN transduced cells (8410±839 vs. 1103±209 cpm; n=3; p=0.00005). Within 7 days 11±1.5% NK emerged from CD34+/Notch+cells compared to 0.8±0.2% of CD34+/eGFP+ control cells (n=5, p=0.0001). NK cell generation peaked at day 28 with a significantly higher expression of CD7 on NK cells (Notch: 75±5% vs. eGFP: 4.5±1%, n=5, p=0.00004), and no B lymphocytes were seen. Analysis of Notch induced NK cells demonstrated early expression of L-selectin and increased expression of CD45RA on all lymphoid progenitors. At 4 weeks, functional testing revealed reduced cytotoxicity against K562 (Notch: 37±0.5% vs. eGFP: 63.5±1.3%; n=7, p=0.007) suggesting immature function. CD34+/Notch+ derived NK lymphocytes also showed diminished acquisition of the lectin-type receptor NKG2A (Notch: 8.3±3% vs. eGFP: 27.4±4.5%; p=0.04) and killer immunoglobulin receptors (Notch: 2.2±0.5% vs. eGFP: 10.8±4: p=0.05). We next asked whether the Notch induced CD7+ precursor was NK restricted or a common NK/T cell precursor. After 5 weeks in culture, a distinct population of CD3+ T-cells emerged (Notch: 18±5% vs. eGFP: 1.6±0.2; n=5, p<0.001%) which were CD4 and CD8 negative and did not express surface TCR a/b or g/d, but expressed high levels pre-T-alpha mRNA. These Notch activated cells were bona fide T-cells based on their capacity to produce IL-2 after PMA/Ca/I stimulation (62.4±4% by intracellular staining) while essentially no IL-2 production occurred from eGFP control cells (1.6±0.2%; p<0.0001). T-cell development was dependent on both Notch and the EL08.1D2 as no T-cells resulted from CD34+/eGFP-Notch in the absence of stroma. These findings suggest that in addition to Notch and exogenous cytokines, other soluble factors are required for T cell development. In conclusion, our data showed that activated Notch pathway leads to differentiation of a common CD7+ lymphoid precursor capable of both early NK cell and T-cell differentiation. This suggests that differences in Notch ligands in local microenvironments (marrow, thymus, lymph node) may be an important mechanism to orchestrate NK and T cell development.

scholarly journals Normal T-Cell Development and Immune Functions in TRIM-Deficient Mice

2006 ◽  
Vol 26 (9) ◽  
pp. 3639-3648 ◽  
Author(s):  
Uwe Kölsch ◽  
Börge Arndt ◽  
Dirk Reinhold ◽  
Jonathan A. Lindquist ◽  
Nicole Jüling ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Subsets ◽  
Immune Functions ◽  
Deficient Mice

ABSTRACT The transmembrane adaptor molecule TRIM is strongly expressed within thymus and in peripheral CD4+ T cells. Previous studies suggested that TRIM is an integral component of the T-cell receptor (TCR)/CD3 complex and might be involved in regulating TCR cycling. To elucidate the in vivo function of TRIM, we generated TRIM-deficient mice by homologous recombination. TRIM−/− mice develop normally and are healthy and fertile. However, the animals show a mild reduction in body weight that appears to be due to a decrease in the size and/or cellularity of many organs. The morphology and anatomy of nonlymphoid as well as primary and secondary lymphoid organs is normal. The frequency of thymocyte and peripheral T-cell subsets does not differ from control littermates. In addition, a detailed analysis of lymphocyte development revealed that TRIM is not required for either positive or negative selection. Although TRIM−/− CD4+ T cells showed an augmented phosphorylation of the serine/threonine kinase Akt, the in vitro characterization of peripheral T cells indicated that proliferation, survival, activation-induced cell death, migration, adhesion, TCR internalization and recycling, TCR-mediated calcium fluxes, tyrosine phosphorylation, and mitogen-activated protein family kinase activation are not affected in the absence of TRIM. Similarly, the in vivo immune response to T-dependent and T-independent antigens as well as the clinical course of experimental autoimmune encephalomyelitis, a complex Th1-mediated autoimmune model, is comparable to that of wild-type animals. Collectively, these results demonstrate that TRIM is dispensable for T-cell development and peripheral immune functions. The lack of an evident phenotype could indicate that TRIM shares redundant functions with other transmembrane adaptors involved in regulating the immune response.

Rac1 and Rac2 GTPases Play Redundant but Critical Role in T-Cell Development and Survival.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3304-3304
Author(s):  
Fukun Guo ◽  
David Hildeman ◽  
David A. Williams ◽  
Yi Zheng
Keyword(s):  
T Cells ◽  
T Cell ◽  
Developmental Stages ◽  
Critical Role ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Subsets ◽  
Actin Dynamics ◽  
Hematopoietic Stem ◽  
Apoptosis Rate

Abstract The Rac subfamily GTPases of the Rho family have been implicated in the control of actin dynamics, cell proliferation, apoptosis, adhesion and migration of many blood cell types including hematopoietic stem/progenitors, neutrophils and macrophages, but their role in T cell development remains poorly understood. T cells from the Rac2 deficient mice appear to mostly undergo normal development, whereas previous constitutively active mutant Rac2 or Rac1 overexpression studies suggest Rac GTPases are required for CD4+ and CD8+ T cell maturation. Using conditional gene targeting, we have achieved specific deletion of Rac1 or Rac1 together with Rac2 in the T cell lineage by cross-breeding the Lck-Cre transgenic mice with the Rac1flox/flox mice that contain a pair of loxP sites sandwiching the exon 1 sequences of Rac1 or the Rac1flox/flox;Rac2−/− mice. We show that similar to Rac2 deficiency, inactivation of Rac1 alone had little effect on various developmental stages of T cells in the animal. However, deletion of both Rac1 and Rac2 significantly affected both the immature CD4−CD8− (2.3 fold increase) and CD4+CD8+ (13% decrease) populations in the mouse thymus and the mature CD4+ and CD8+ populations in the thymus and spleen (Table). These developmental defects are associated with proliferation defects of thymocytes and splenocytes in response to ConA or PMA/ionomycin stimulation and deficient survival of various T cell populations at different developmental stages (Table). Together, these data show that Rac1 and Rac2 play overlapping and obligatory roles in T-cell development and serve as important cell survival regulators at various stages. Table. Frequency and apoptosis rate of different T-cell subsets in thymocytes and splenocytes T cell subsets WT (n=10) Rac1−/− (n=6) Rac1−/−Rac2−/−(n=6) Total thymocyte number (×106) 101.3±30.0 98.0±25.0 44.7±25.5 CD4−CD8− thymocyte frequency (%) 5.5±1.9 4.5±0.7 12.7±4.3 apoptosis rate (%) 20.1±2.2 15.0±1.3 CD4+CD8+ thymocyte frequency (%) 76.2±3.2 77.3±4.1 66.2±5.4 apoptosis rate (%) 18.8±4.3 27.9±2.8 CD4+ thymocyte frequency (%) 14.5±3.4 14.4±2.4 7.9±2.3 apoptosis rate (%) 13.3±2.3 21.5±4.5 CD8+ thymocyte frequency (%) 3.9±1.2 3.8±1.0 13.2±2.2 apoptosis rate (%) 12.5±2.2 8.8±1.1 Total splenocyte number (×106) 60.4±21.8 62.0±13.0 51.1±28.9 CD4+TCRβ+ splenocyte frequency (%) 9.7±2.2 8.0±2.3 3.2±1.1 apoptosis rate (%) 15.1±3.1 27.5±6.9 CD8+TCRβ+ splenocyte frequency (%) 3.2±0.8 2.4±0.9 0.6±0.4 apoptosis rate (%) 13.1±3.0 24.5±6.4

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.

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