scholarly journals Ontogenic Development of Th1 and Th2 Cytokine Capabilities in Random Bred Mice

2002 ◽  
Vol 9 (1) ◽  
pp. 1-8
Author(s):  
Omar R. Fagoaga ◽  
Sandra L. Nehlsen-Cannarella
Keyword(s):  
T Cells ◽  
Cytokine Production ◽  
Cd4 Cells ◽  
Adult Mice ◽  
Th2 Cytokine ◽  
Ontogenic Development ◽  
Th1 Cytokine ◽  
Antigen Presenting ◽  
Allogeneic Stimulation

Neonatal mouse Th1 capabilities mature by postnatal day 5. Neonatal T cells have been reported to exhibit a bias towards Th2 cytokine production when co-cultured with adult antigen presenting cells (APC). We studied mouse T cells co-cultured with contemporary APC to evaluate neonatal cytokine production capabilities. In response to allogeneic stimulation, T cells co-cultured with contemporary APC from day 5 pups produced 37-fold greater IFNγ and 1.4-fold greater IL-2 levels than day 20 weanling mice. After CD3 ligation, cells from day 5 pups produced 4- (IL-2) and 10-fold (IFNγ) greater levels than adults (day 45), and concentrations were 27- (IL-2) and 18-fold (IFNγ) higher than with allogeneic stimulation alone. On average, the percent difference in concentrations was 418 (IL-4), 286 (IL-2) and 1140% (IFNγ) higher in unseparated spleen cells than in isolated splenic CD4 cells and APC. These results demonstrate that, in response to allogeneic stimulation with or without CD3 ligation, lymphocytes of neonatal mice (day 5) have the capacity to produce equivalent or greater TcR-dependent Th1 cytokine (IL-2 and IFNγ) levels than adult mice. Findings also support the idea that the reported Th2 bias of neonatal T cells may be the result of in vitro manipulation and choice of mouse strain, not of an inherent bias.

scholarly journals Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

1992 ◽  
Vol 176 (5) ◽  
pp. 1431-1437 ◽  
Author(s):  
M Croft ◽  
D D Duncan ◽  
S L Swain
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 Cells ◽  
Peptide Antigen ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

scholarly journals Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells

Blood ◽  
1995 ◽  
Vol 86 (9) ◽  
pp. 3479-3486 ◽  
Author(s):  
LM Webb ◽  
M Feldmann
Keyword(s):  
T Cells ◽  
Cytokine Production ◽  
Critical Role ◽  
Th2 Cytokines ◽  
T Helper ◽  
Cd4 Cells ◽  
Th2 Cytokine ◽  
Cd28 Costimulation ◽  
Costimulatory Pathway

CD28 is a major costimulatory signal receptor for T cells. We have used human naive CD4+ cells from cord blood to analyze the effect of the CD28/B7 costimulatory pathway on development of T helper (Th) subsets. We show that CD28 costimulation is critical for development of the Th2 cytokine-producing cells and that in the absence of CD28 costimulation, cells are not primed to produce Th2 cytokines and consequently “default” to the Th1 subset, independent of the presence of exogenous cytokines. After CD28 costimulation, cells differentiate into a subset that produces Th2 cytokines. However, further CD28 costimulation is not required to maintain Th2 cytokine production. We conclude that D28 costimulation is critical for the development of Th0 and Th2 subsets, but not for the maintenance of cytokine production.

T-Cell Receptor-Independent Activation of Clonal Th2 Cells Associated With Chronic Hypereosinophilia

Blood ◽  
1999 ◽  
Vol 94 (3) ◽  
pp. 994-1002 ◽  
Author(s):  
Florence Roufosse ◽  
Liliane Schandené ◽  
Catherine Sibille ◽  
Bernard Kennes ◽  
André Efira ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Interleukin 5 ◽  
Costimulatory Signals ◽  
Antigen Presenting ◽  
Full Activation

We recently observed a clonal expansion of CD3−CD4+ T cells secreting Th2-type cytokines in patients presenting chronic hypereosinophilia. As clonal T cells isolated from such patients did not spontaneously secrete cytokines in vitro, we reasoned that costimulatory signals delivered by antigen-presenting cells might be required to induce their full activation. To address this question, we investigated in two such patients the responses of CD3−CD4+ T cells to dendritic cells (DC). DC elicited proliferation and production of interleukin-5 (IL-5) and IL-13 by clonal cells from patient 1 and upregulated their expression of CD25 (IL-2R-). These effects were abolished when blocking monoclonal antibodies (MoAbs) against IL-2R- and IL-2 were added to cocultures, indicating critical involvement of an autocrine IL-2/IL-2R pathway. Cells from patient 2 were stimulated by DC to produce Th2 cytokines only when rIL-2 or rIL-15 was added to cocultures. In both patients, addition of inhibitory MoAbs against B7-1/B7-2 or CD2 to cocultures resulted in dramatic reduction of cytokine production and inhibited CD25 upregulation. Thus, TCR/CD3-independent activation of clonal Th2 cells by DC is an IL-2–dependent process, which requires signaling through CD2 and CD28.

scholarly journals Interferon γ Enhances Both In Vitro and In Vivo Priming of CD4+ T Cells for IL-4 Production

2004 ◽  
Vol 199 (12) ◽  
pp. 1619-1630 ◽  
Author(s):  
Petr Bocek ◽  
Gilles Foucras ◽  
William E. Paul
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interferon Γ ◽  
T Helper ◽  
Classical Studies ◽  
Th1 Cytokine ◽  
Ifn Γ ◽  
Antigen Presenting

Classical studies have demonstrated that in vitro priming of naive CD4 T cells to become T helper (Th)2 cells is strikingly dependent on interleukin (IL)-4, whereas priming for interferon (IFN)γ production is IL-12/IFNγ-dependent. Therefore, it was quite surprising when we noted that priming of naive C57BL/6 CD4+ cells to become IL-4 producers was substantially inhibited by the addition of anti-IFNγ antibodies. This was true using immobilized anti-CD3 and anti-CD28 antibodies or soluble anti-CD3/anti-CD28 and antigen-presenting cells in the presence or absence of added IL-4. Priming of CD4 T cells from IFNγ−/− C57BL/6 mice with immobilized anti-CD3 and anti-CD28 resulted in limited production of IL-4, even with the addition of 1,000 U/ml of IL-4. Titrating IFNγ into such cultures showed a striking increase in the proportion of T cells that secreted IL-4 upon challenge; this effect was completely IL-4–dependent in that it was blocked with anti–IL-4 antibody. Thus, IFNγ plays an unanticipated but substantial role in Th2 priming, although it is an important Th1 cytokine, and under certain circumstances a Th1 inducer.

scholarly journals Preferential Th1 Cytokine Profile of Phosphoantigen-Stimulated Human Vγ9Vδ2 T Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Margaret R. Dunne ◽  
Bozgana A. Mangan ◽  
Laura Madrigal-Estebas ◽  
Derek G. Doherty
Keyword(s):  
T Cells ◽  
Tumour Necrosis ◽  
Cytokine Production ◽  
Innate And Adaptive Immunity ◽  
Multiple Functions ◽  
Th1 Cytokine ◽  
Vγ9vδ2 T Cells ◽  
Necrosis Factor ◽  
Unique Ability

Human Vγ9Vδ2 T cells recognise pyrophosphate-based antigens (phosphoantigens) and have multiple functions in innate and adaptive immunity, including a unique ability to activate other cells of the immune system. We used flow cytometry and ELISA to define the early cytokine profiles of Vγ9Vδ2 T cells stimulated in vitro with isopentenyl pyrophosphate (IPP) and (E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate (HMB-PP) in the absence and presence of IL-2 and IL-15. We show that fresh Vγ9Vδ2 T cells produce interferon-γ(IFN-γ) and tumour necrosis factor-α(TNF-α) within 4 hours of stimulation with phosphoantigen, but neither IL-10, IL-13, nor IL-17 was detectable up to 72 hours under these conditions. Cytokine production was not influenced by expression or lack, thereof, of CD4 or CD8. Addition of IL-2 or IL-15 caused expansion of IFN-γ-producing Vγ9Vδ2 T cells, but did not enhance IFN-γsecretion after 24–72 hours. Thus, phosphoantigen-stimulated Vγ9Vδ2 T cells have potential as Th1-biasing adjuvants for immunotherapy.

scholarly journals TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xin Chen ◽  
Yingjie Nie ◽  
Haitao Xiao ◽  
Zhaoxiang Bian ◽  
Anthony J. Scarzello ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Colitis ◽  
Effector T Cells ◽  
Functional Stability ◽  
Cd4 Cells ◽  
Th1 Cytokine ◽  
Mechanistic Basis ◽  
Rag 1

Abstract There is now compelling evidence that TNFR2 is constitutively expressed on CD4+ Foxp3+ regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4+ Foxp3− effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2−/− mice into Rag 1−/− recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naïve CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naïve CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells.

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

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