Comparative Effects of Interleukin-12 and Interleukin-4 on Cytokine Responses by Antigen-Stimulated Memory CD4+ T Cells of Cattle: IL-12 Enhances IFN-gamma Production, Whereas IL-4 Has Marginal Effects on Cytokine Expression

1999 ◽  
Vol 19 (7) ◽  
pp. 741-749 ◽  
Author(s):  
Wenbin Tuo ◽  
D. Mark Estes ◽  
Wendy C. Brown
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Expression ◽  
Interleukin 4 ◽  
Interleukin 12 ◽  
Ifn Gamma ◽  
Cytokine Responses ◽  
Marginal Effects ◽  
Memory Cd4 T Cells

scholarly journals Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.

1994 ◽  
Vol 179 (2) ◽  
pp. 447-456 ◽  
Author(s):  
S L Reiner ◽  
S Zheng ◽  
Z E Wang ◽  
L Stowring ◽  
R M Locksley
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Interleukin 12 ◽  
Insect Vector ◽  
T Helper 1 ◽  
Ifn Gamma ◽  
Effector Cells

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism.

scholarly journals The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.

1992 ◽  
Vol 176 (4) ◽  
pp. 1091-1098 ◽  
Author(s):  
R A Seder ◽  
W E Paul ◽  
M M Davis ◽  
B Fazekas de St Groth
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Ifn Gamma

To study the factors that determine whether CD4+ T cells produce interleukin 4 (IL-4) or interferon gamma (IFN-gamma) upon stimulation we used a system allowing naive T cells to be primed in vitro by specific antigen. Dense CD4+ T cells were purified from mice that expressed transgenes encoding a T cell receptor specific for pigeon cytochrome C peptide 88-104 in association with I-Ek. These T cells produced very limited amounts of IL-4 and IFN-gamma upon immediate challenge with 88-104 and antigen-presenting cells (APC). However, after an initial "priming" culture in which they were incubated for 4 d in the presence of 88-104, APC, and 1,000 U/ml IL-4, the T cells acquired the capacity to produce substantial amounts of IL-4 upon rechallenge but made very little IFN-gamma. Cells primed in the absence of IL-4 produced IFN-gamma upon rechallenge but virtually no IL-4. The inhibitory effect of IL-4 on IFN-gamma production did not appear to be mediated by the induction of IL-10 production since IL-10 addition to initial cultures did not suppress priming for IFN-gamma production, nor did anti-IL-10 block the inhibitory effect of IL-4. IFN-gamma itself did not increase priming for IFN-gamma production, nor did anti-IFN-gamma reduce such priming. IFN-gamma did, however, diminish priming for IL-4 production when limiting amounts of IL-4 (100 U/ml) were used in the initial culture. The dominant effect of IL-4 in determining the lymphokine-producing phenotype of primed cells was observed with dendritic cells (DC), activated B cells, and I-Ek-transfected fibroblasts as APC. However, the different APC did vary in their potency, with DC being superior to activated B cells, which were superior to transfected fibroblasts.

scholarly journals Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals.

1993 ◽  
Vol 178 (6) ◽  
pp. 2123-2130 ◽  
Author(s):  
H Secrist ◽  
C J Chelen ◽  
Y Wen ◽  
J D Marshall ◽  
D T Umetsu
Keyword(s):  
T Cells ◽  
Allergic Rhinitis ◽  
Cd4 T Cells ◽  
Allergen Immunotherapy ◽  
Subcutaneous Administration ◽  
Interleukin 4 ◽  
Clinical Effects ◽  
Cytokine Profiles ◽  
Memory Cd4 T Cells

Allergen specific CD4+ T cell clones generated from allergic individuals have been shown to produce increased levels of the cytokine interleukin 4 (IL-4), compared to allergen specific clones generated from nonallergic individuals. This difference between CD4+ T cells from allergic and nonallergic individuals with regard to cytokine production in response to allergen is thought to be responsible for the development of allergic disease with increased IgE synthesis in atopic individuals. We examined the production of IL-4 in subjects with allergic rhinitis and in allergic individuals treated with allergen immunotherapy, a treatment which involves the subcutaneous administration of increasing doses of allergen and which is highly effective and beneficial for individuals with severe allergic rhinitis. We demonstrated that the quantity of IL-4 produced by allergen specific memory CD4+ T cells from allergic individuals could be considerably reduced by in vivo treatment with allergen (allergen immunotherapy). Immunotherapy reduced IL-4 production by allergen specific CD4+ T cells to levels observed with T cells from nonallergic subjects, or to levels induced with nonallergic antigens such as tetanus toxoid. In most cases the levels of IL-4 produced were inversely related to the length of time on immunotherapy. These observations indicate that immunotherapy accomplishes its clinical effects by reducing IL-4 synthesis in allergen specific CD4+ T cells. In addition, these observations indicate that the cytokine profiles of memory CD4+ T cells can indeed be altered by in vivo therapies. Thus, the cytokine profiles of memory CD4+ T cells are mutable, and are not fixed as had been suggested by studies of murine CD4+ memory T cells. Finally, treatment of allergic diseases with allergen immunotherapy may be a model for other diseases which may require therapies that alter inappropriate cytokine profiles of memory CD4+ T cells.

scholarly journals The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model.

1995 ◽  
Vol 182 (5) ◽  
pp. 1579-1584 ◽  
Author(s):  
N A Hosken ◽  
K Shibuya ◽  
A W Heath ◽  
K M Murphy ◽  
A O'Garra
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Primary Cultures ◽  
Buoyant Density ◽  
Interleukin 4 ◽  
Cell Phenotype ◽  
T Helper ◽  
Ifn Gamma ◽  
Antigen Dose ◽  
Alpha Beta

The dose of foreign antigen can influence whether a cell-mediated or humoral class of immune response is elicited, and this may be largely accounted for by the development of CD4+ T helper cells (Th) producing distinct sets of cytokines. The ability of antigen dose to direct the development of a Th1 or Th2 phenotype from naive CD4+ T cells, however, has not been demonstrated. In this report, we show that the antigen dose used in primary cultures could directly affect Th phenotype development from naive DO11.10 TCR-alpha beta-transgenic CD4+ T cells when dendritic cells or activated B cells were used as the antigen-presenting cells. Consistent with our previous findings, midrange peptide doses (0.3-0.6 microM) directed the development of Th0/Th1-like cells, which produced moderate amounts of interferon gamma (IFN-gamma). As the peptide dose was increased, development of Th1-like cells producing increased amounts of IFN-gamma was initially observed. At very high (> 10 microM) and very low (< 0.05 microM) doses of antigenic peptide, however, a dramatic switch to development of Th2-like cells that produced increasing amounts of interleukin 4 (IL-4) and diminishing levels of IFN-gamma was observed. This was true even when highly purified naive, high buoyant density CD4+ LECAM-1hi T cells were used, ruling out a possible contribution from contaminating "memory" phenotype CD4+ T cells. Neutralizing anti-IL-4 antibodies completely inhibited the development of this Th2-like phenotype at both high and low antigen doses, demonstrating a requirement for endogenous IL-4. Our findings suggest that the antigen dose may affect the levels of endogenous cytokines such as IL-4 in primary cultures, resulting in the development of distinct Th cell phenotypes.

scholarly journals CD28-mediated costimulation of interleukin 2 (IL-2) production plays a critical role in T cell priming for IL-4 and interferon gamma production.

1994 ◽  
Vol 179 (1) ◽  
pp. 299-304 ◽  
Author(s):  
R A Seder ◽  
R N Germain ◽  
P S Linsley ◽  
W E Paul
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Gamma ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Interleukin 2 ◽  
Interleukin 4 ◽  
Accessory Cell ◽  
Ifn Gamma ◽  
Cd28 Costimulation

Naive T cells require interleukin 4 (IL-4) to develop into IL-4-producing T cells and IL-4 blocks development of such cells into interferon gamma (IFN-gamma) producers. Prior studies in accessory cell-independent priming systems using antireceptor antibodies as agonists have demonstrated that IL-2 is also necessary for the development of IL-4-producing cells under these culture conditions. Here we have examined the role of IL-2 and the CD28 costimulation pathway in priming for IL-4 and IFN-gamma production using a more physiologic model. This involved antigen presentation by accessory cells to naive CD4+ T cells from transgenic mice whose cells express a T cell receptor (TCR) specific for a cytochrome c peptide in association with I-Ek. With splenic antigen-presenting cells (APCs), inhibition of CD28 costimulation by the fusion protein CTLA4-immunoglobulin (Ig) blocked effective priming. Similarly, transfected fibroblasts expressing both MHC class II and the CD28 ligand B7 could prime for IL-4 production and such priming also was blocked by CTLA4-Ig. However, APCs deficient in CD28 ligands also could prime TCR transgenic T cells to become IL-4 producers if an exogenous source of IL-2, as well as IL-4, was provided, and the inhibition of priming seen with splenic or transfected fibroblast APCs in the presence of CTLA4-Ig could be reversed by addition of IL-2. Likewise, priming for IFN-gamma production could be blocked by CTLA4-Ig and reversed by IL-2. Thus, we conclude that IL-2 plays a critical role in priming naive CD4+ T cells to become IL-4 or IFN-gamma producers. Engagement of the CD28 pathway, although normally important in such priming, is unnecessary in the presence of exogenous IL-2.

scholarly journals Antibodies to interleukin 12 abrogate established experimental colitis in mice.

1995 ◽  
Vol 182 (5) ◽  
pp. 1281-1290 ◽  
Author(s):  
M F Neurath ◽  
I Fuss ◽  
B L Kelsall ◽  
E Stüber ◽  
W Strober
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Murine Model ◽  
Cd4 T Cells ◽  
Intestinal Inflammation ◽  
Interleukin 12 ◽  
Trinitrobenzene Sulfonic Acid ◽  
Ifn Gamma ◽  
Chronic Intestinal Inflammation

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.

scholarly journals Interleukin 12 and Interleukin 4 Control T Cell Adhesion to Endothelial Selectins through Opposite Effects on α1,3-fucosyltransferase VII Gene Expression

1998 ◽  
Vol 188 (12) ◽  
pp. 2225-2231 ◽  
Author(s):  
Amy J. Wagers ◽  
Christopher M. Waters ◽  
Lloyd M. Stoolman ◽  
Geoffrey S. Kansas
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Single Gene ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
Th 1

The α1,3-fucosyltransferase, FucT-VII, is crucial for the formation of ligands for all three selectins, and its expression regulates the synthesis of these ligands. Short-term polarized T helper (Th)1, but not Th2 or naive CD4+ T cells, can home to sites of inflammation, but the molecular basis for this difference has remained unclear. Here we show that naive CD4+ T cells do not express FucT-VII and fail to bind vascular selectins. We also show that when CD4+ T cells are activated in the presence of the Th1 polarizing cytokine interleukin (IL)-12, levels of FucT-VII mRNA and binding to E- and P-selectin are significantly augmented. In contrast, activation of CD4+ T cells in the presence of IL-4, a Th2 polarizing cytokine, inhibited FucT-VII expression and binding to vascular selectins. T cell activation upregulated expression of the Core2 transferase, C2GnT, equivalently regardless of the presence or absence of polarizing cytokines. These data indicate that the selective ability of Th1 cells, as opposed to Th2 cells or naive CD4+ T cells, to recognize vascular selectins and home to sites of inflammation is controlled principally by the expression of a single gene, FucT-VII.

scholarly journals Induction of interleukin 12 responsiveness is impaired in anergic T lymphocytes.

1994 ◽  
Vol 179 (3) ◽  
pp. 1065-1070 ◽  
Author(s):  
H Quill ◽  
A Bhandoola ◽  
G Trinchieri ◽  
J Haluskey ◽  
D Peritt
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Proliferative Response ◽  
Interleukin 12 ◽  
T Helper 1 ◽  
Ifn Gamma ◽  
Enhanced Production

The cytokine, interleukin 12 (IL-12), stimulates both natural killer cells and T cells to proliferate and to secrete interferon gamma (IFN-gamma). The T cell proliferative response to IL-12 must be induced and is evident after T cell receptor-mediated stimulation. As reported here, tolerant CD4+ T cells and clones, that are anergic for IL-2 production, are also anergic for induction of the proliferative response to IL-12. Murine T helper 1 clones tolerized in vitro, as well as anergic CD4+ T cells isolated from mice tolerized to the Mls-1a antigen (Ag) in vivo, demonstrated defective induction of proliferation to IL-12 upon restimulation with Ag. IL-12-enhanced production of IFN-gamma was observed in both control and anergic cells after Ag/antigen-presenting cell (APC) activation, although total IFN-gamma secretion by anergic cells was less than that produced by control cells, even in the presence of IL-12. These data indicate that T cell clonal anergy results in profound inhibition of proliferative responses, since the autocrine growth factor, IL-2, is not produced, and the APC-derived cytokine, IL-12, is not an effective stimulus for anergic T cell proliferation.

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