Interleukin‐12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (T<sub>h</sub>1) but not on T<sub>h</sub>2 cells

Germann, Tieno; Gately, Maurice K.; Schoenhaut, David S.; Lohoff, Michael; Mattner, Frank; Fischer, Susanne; Jin, Shenchu; Schmitt, Edgar; Rüde, Erwin

doi:10.1002/eji.1830230805

Cited by 239 publications

(158 citation statements)

References 72 publications

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“…Some cytokines such as IL-4 and IL-12 contribute to the differential growth of the subsets. For example, IL-4 preferentially promotes the activation and growth of TH2 cells (34,35); IL-12 stimulates TH1 cells (36). The local production of cytokines by regulatory cells at sites of inflammation may serve to effect antigen-specific immunoregulation.…”

Section: Discussionmentioning

confidence: 99%

CD8⁺T cells control the TH phenotype of MBP-reactive CD4⁺T cells in EAE mice

Jiang

Braunstein

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

117

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T o regulate the immune response and dampen the potential for autoimmunity, the immune system has evolved several mechanisms to down-regulate and control the outgrowth and differentiation of activated CD4 ϩ T cells. One level of control, mediated during the initial interaction of the CD4 ϩ T cell with MHC͞peptide complexes on the surface of antigen-presenting cells, determines whether T cell activation, anergy, or apoptosis will ensue (1-3). A second level of control, mediated by cytokines, regulates the growth and differentiation of activated CD4 ϩ T cells. Different cytokines secreted by CD4 ϩ or CD8 ϩ T cells either stimulate or inhibit CD4 ϩ T cell proliferation and determine whether a naïve T helper (TH) precursor cell differentiates as an IFN-␥-producing TH1 cell or as an IL-4-and IL-10-producing TH2 cell (4-6). A third level of control resides in the regulatory T cells including both CD4 ϩ (7) and CD8 ϩ (8) T cell populations. For example, ample data demonstrate the ability of CD8 ϩ T cells to regulate CD4 ϩ T cell responses (9-13). These effects of CD8 ϩ T cells have been mostly attributed, in recent years, to the CD8 ϩ T cells' secretion of cytokines (14).In addition to identifying cytokines as potential effectors of immune regulation by CD8 ϩ T cells, other studies have identified specific cognate interactions between regulatory CD8 ϩ T cells and activated CD4 ϩ T cells. For example, during antigen-or superantigen-driven CD4 ϩ T cell responses in vivo, CD8 ϩ T cells emerge that specifically regulate CD4 ϩ T cells in a T cell antigen receptor (TCR) V␤-specific manner (15, 16). These CD8 ϩ T cells preferentially recognize antigen-activated CD4 ϩ T cell clones expressing certain TCR V␤ molecules and are restricted by the class I-b MHC molecule Qa-1. Unlike conventional MHC class I-a molecules, Qa-1 molecules are expressed only at low levels on resting T cells but are increased after antigen activation (17). These data are consistent with a model of specific immunoregulation in which after antigen activation CD4 ϩ T cells express membrane Qa-1͞TCRV␤ motifs that are recognized by the ␣␤ TCR expressed by precursor regulatory CD8 ϩ T cells. These CD8 ϩ T cells are induced to differentiate and down-regulate CD4 ϩ T cells expressing the particular Qa-1͞TCRV␤ motifs.A prediction of this model is that Qa-1-restricted, V␤-specific regulatory CD8 ϩ T cells will be induced by ''vaccination'' of animals with antigen-activated CD4 ϩ T cells, using T cell vaccination (TCV) protocols known to prevent autoimmune disease in animal models (18,19). In this regard, we have shown that Qa-1-restricted, V␤-specific CD8 ϩ cytotoxic T cell lines are induced by TCV (16). Moreover, we isolated a CD8 ϩ T hybridoma clone from a T cell-vaccinated mouse that preferentially recognizes CD4 ϩ V␤8 ϩ but not CD4 ϩ V␤6 ϩ myelin basic protein (MBP)-reactive clones in a Qa-1-restricted fashion (16). In this current study, we further confirmed this prediction by investigating an experimental autoimmune encephalomyelitis (EAE) model system in wh...

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Section: Discussionmentioning

confidence: 99%

CD8⁺T cells control the TH phenotype of MBP-reactive CD4⁺T cells in EAE mice

Jiang

Braunstein

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

117

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“…IL-12 is a potent costimulator for the development of Th1 cells (45). This is accomplished by IFN-␥ induction in Th1 cells (46,47) and promotion of Ag-dependent proliferation of activated T lymphocytes (48). SP is also capable of directly inducing T cell IFN-␥ that is known to suppress IL-4 and the development of a Th2 cell phenotype as well as of enhancing mitogen-induced IFN-␥ in human PBMC (49,50).…”

Section: Discussionmentioning

confidence: 99%

Neutral Endopeptidase Terminates Substance P-Induced Inflammation in Allergic Contact Dermatitis

Scholzen

Steinhoff

Bonaccorsi

et al. 2001

The Journal of Immunology

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Sensory nerve-derived neuropeptides such as substance P demonstrate a number of proinflammatory bioactivities, but less is known about their role in inflammatory skin disease. The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP−/− knockout and NEP+/+ wild-type mice and compared with the irritant contact dermatitis response in these animals. NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels. The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augmented ACD response in NEP−/− animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin. Similar to NEP−/− mice, the acute inhibition of NEP in NEP+/+ animals resulted in an augmented ACD response. In contrast to the ACD responses, little differences were observed in the irritant contact dermatitis response of NEP−/− compared with NEP+/+ animals after epicutaneous application of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathogenesis of ACD.

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“…One of the most important properties of IL-12 is its ability to induce the production of large amounts of IFN-␥ from resting and activated T and NK cells (1,2). Via induction of IFN-␥, IL-12 exerts many immunoregulatory effects on both lymphoid and nonlymphoid cells to promote cell-mediated immunity, thus making IL-12 an effective agent to treat cancer and infectious diseases (3)(4)(5).…”

Section: Suppression Of Immune Response and Protective Immunity To A mentioning

confidence: 99%

Suppression of Immune Response and Protective Immunity to a Japanese Encephalitis Virus DNA Vaccine by Coadministration of an IL-12-Expressing Plasmid

Chen

Pan

Huan

et al. 2001

The Journal of Immunology

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IL-12 plays a central role in both innate and acquired immunity and has been demonstrated to potentiate the protective immunity in several experimental vaccines. However, in this study, we show that IL-12 can be detrimental to the immune responses elicited by a plasmid DNA vaccine. Coadministration of the IL-12-expressing plasmid (pIL-12) significantly suppressed the protective immunity elicited by a plasmid DNA vaccine (pE) encoding the envelope protein of Japanese encephalitis virus. This suppressive effect was associated with marked reduction of specific T cell proliferation and Ab responses. A single dose of pIL-12 treatment with plasmid pE in initial priming resulted in significant immune suppression to subsequent pE booster immunization. The pIL-12-mediated immune suppression was dose dependent and evident only when the IL-12 gene was injected either before or coincident with the pE DNA vaccine. Finally, using IFN-γ gene-disrupted mice, we showed that the suppressive activity of the IL-12 plasmid was dependent upon endogenous production of IFN-γ. These results demonstrate that coexpression of the IL-12 gene can sometimes produce untoward effects to immune responses, and thus its application as a vaccine adjuvant should be carefully evaluated.

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Interleukin‐12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (T_h1) but not on T_h2 cells

Cited by 239 publications

References 72 publications

CD8⁺T cells control the TH phenotype of MBP-reactive CD4⁺T cells in EAE mice

CD8⁺T cells control the TH phenotype of MBP-reactive CD4⁺T cells in EAE mice

Neutral Endopeptidase Terminates Substance P-Induced Inflammation in Allergic Contact Dermatitis

Suppression of Immune Response and Protective Immunity to a Japanese Encephalitis Virus DNA Vaccine by Coadministration of an IL-12-Expressing Plasmid

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Interleukin‐12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells

Cited by 239 publications

References 72 publications

CD8+T cells control the TH phenotype of MBP-reactive CD4+T cells in EAE mice

CD8+T cells control the TH phenotype of MBP-reactive CD4+T cells in EAE mice

Neutral Endopeptidase Terminates Substance P-Induced Inflammation in Allergic Contact Dermatitis

Suppression of Immune Response and Protective Immunity to a Japanese Encephalitis Virus DNA Vaccine by Coadministration of an IL-12-Expressing Plasmid

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Interleukin‐12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (T_h1) but not on T_h2 cells

CD8⁺T cells control the TH phenotype of MBP-reactive CD4⁺T cells in EAE mice

CD8⁺T cells control the TH phenotype of MBP-reactive CD4⁺T cells in EAE mice