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Biomedical subjects

T R Mosmann

Publications and source records attributed to T R Mosmann.

At least 55 records · Page 3Linked to original sources
PubMed1991

Cytokines: is there biological meaning?

In the immune system, amidst the bewildering array of cytokine functions, it is sometimes difficult to discern the relative physiological importance of functions that have been determined in tissue culture. Cytokine functions are indeed complex, but the analysis of relatively simple regulatory networks suggests that activities determined in vitro are highly relevant to genuine physiological functions.

Animals↗
PubMed1991

The role of IL-10 in crossregulation of TH1 and TH2 responses.

The identification of helper T (TH)-cell subsets has greatly improved understanding of the regulation of immune effector functions. In addition to controlling humoral and delayed-type hypersensitivity responses, these subsets crossregulate by secreting mutually inhibitory cytokines. In this review, Tim Mosmann and Kevin Moore examine these phenomena and in particular the role of interleukin 10, a cytokine secreted by TH2 cells that inhibits TH1-cell function.

Animals↗
PubMed1991

Functional diversity of T lymphocytes due to secretion of different cytokine patterns.

Different helper T cell subsets secrete different patterns of cytokines when stimulated by antigen. The TH1 and TH2 subsets differ in the secretion of at least eight cytokines, and three or more other cytokine secretion patterns also exist among both mouse and human T cell clones. Several properties of strong immune responses suggest that at least the TH1 and TH2 phenotypes can be present in vivo. As cytokines are major determinants of the functions of the T cells that produce them, these patterns lead to different properties of the T cell subsets. TH1 cells mediate several functions connected with cytotoxicity and local inflammatory reactions, and so these T cells are particularly effective at combating viruses and intracellular bacteria and parasites. TH2 cells are much more effective at stimulating B cells to produce antibody, and so should be more effective against free-living bacteria, and in inducing protective humoral immunity. Antibody and delayed inflammatory reactions are often mutually exclusive during immune responses, and this can be at least partially explained by cross-inhibition of TH1 and TH2 cells. A newly discovered cytokine, IL10, has been implicated as one of the cross-regulatory cytokines, as this TH2 product inhibits cytokine synthesis by TH1 cells.

Animals↗
PubMed1991

Regulation of immune responses by T cells with different cytokine secretion phenotypes: role of a new cytokine, cytokine synthesis inhibitory factor (IL10).

Subsets of T cells, defined by the patterns of cytokines that they secrete, show important functional differences, and appear to be at least partly responsible for the different immune responses induced by various pathogens. Two very distinct subsets, TH1 and TH2, are mutually inhibitory, and a newly discovered cytokine, IL10, is one of the mediators of this cross-regulation. IL10 inhibits the synthesis of cytokines by TH1 cells but not TH2 cells. Since TH2 cells produce IL4 and IL5, which lead to some of the major manifestations of allergy, it is likely that IL10 production biases an immune response towards allergy.

Animals↗
PubMed1990

IL-10, a novel growth cofactor for mature and immature T cells.

We identified a new cytokine, B cell-derived T cell growth factor (B-TCGF), that is produced by a murine B cell lymphoma and induces proliferation of mature and immature thymocytes in the presence of IL-2 and IL-4. Both adult and day 15 fetal thymocytes (CD4-8-, CD4+8-, CD4-8+) proliferate strongly in the presence of IL-2, IL-4, and B-TCGF. B-TCGF alone does not stimulate thymocyte proliferation. B-TCGF appears to be identical to a novel cytokine whose cDNA was recently isolated at our institution, cytokine synthesis-inhibitory factor (CSIF; IL-10). rIL-10 has B-TCGF activity, and mAb specific for IL-10 inhibit the B-TCGF activity present in CH12 supernatants. Further studies have shown that day 15 fetal thymocytes cultured in the presence of IL-10, IL-2, and IL-4 remain CD4- and CD8- but exhibit increased CD3 expression. Adult CD4- CD8- thymocytes cultured under the same conditions proliferate whether they are CD3+ or CD3-. The CD3- population becomes enriched in CD3+ cells after 4 days of culture. IL-10 is secreted by day 15 fetal thymocytes, adult thymocytes, and adult splenocytes when stimulated via their TCR. IL-10 is strongly homologous to the EBV gene BCRFI, and BCRFI has CSIF activity. In contrast to IL-10, BCRFI does not exhibit detectable thymocyte-stimulating activity, suggesting the existence of at least two functional epitopes on the IL-10 molecule.

Animals↗
PubMed1990

Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells.

Highly purified, small dense splenic B cells from unstimulated mice showed increased expression of class II major histocompatibility complex (MHC) antigens and enhanced viability when cultured with affinity-purified recombinant interleukin 10 (rIL-10), compared with B cells cultured in medium alone. These responses were blocked by a monoclonal antibody (mAb) specific for IL-10, but not by an isotype-matched control antibody. IL-10 did not upregulate the expression of Fc epsilon receptors (CD23) or class I MHC antigens on small dense B cells or induce their replication as monitored by [3H]thymidine incorporation. While these B cell-stimulatory properties of IL-10 are also mediated by IL-4, the two cytokines appear to act independently in these assays; anti-IL-10 antibodies blocked IL-10 but not IL-4-mediated B cell viability enhancement, and vice versa. Similarly, since IL-4 upregulates CD23 on small dense B cells, the inability of IL-10 to do so argues against its acting via endogenously generated IL-4. Finally, IL-10 did not upregulate class II MHC antigens on B cells from X chromosome-linked immunodeficiency (XID) mice, while the same cells showed normal upregulation of class II antigens in response to IL-4. This report also extends our understanding of the relationship between IL-10 and the highly homologous Epstein-Barr virus (EBV)-encoded Bam HI fragment C rightward reading frame no. 1 (BCRFI) protein. It has previously been shown that BCRFI protein exhibits the cytokine synthesis inhibitory activity of IL-10. This report indicates that BCRFI protein also enhances in vitro B cell viability, but does not upregulate class II MHC antigens on B cells. One explanation for these data is that IL-10 contains at least two functional epitopes, only one of which has been conserved by EBV.

Animals↗
PubMed1990

Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1.

Cytokine synthesis inhibitory factor (CSIF; interleukin-10), a product of mouse TH2 T cell clones that inhibits synthesis of cytokines by mouse TH1 T cell clones, exhibits extensive sequence similarity to an uncharacterized open reading frame in the Epstein-Barr virus BCRF1. Recombinant BCRF1 protein mimics the activity of interleukin-10, suggesting that BCRF1 may have a role in the interaction of the virus with the host's immune system.

Animals↗
PubMed1990

Isolation of monoclonal antibodies specific for IL-4, IL-5, IL-6, and a new Th2-specific cytokine (IL-10), cytokine synthesis inhibitory factor, by using a solid phase radioimmunoadsorbent assay.

Hybridomas were produced from a rat that was immunized with partially purified proteins from supernatants of induced Th2 cells. These preparations were enriched for cytokine synthesis inhibitory factor (CSIF, IL-10). The mAb in the supernatants were screened by a solid phase radioimmunoadsorbent assay using 35S-methionine-labeled secreted proteins from a lectin-stimulated Th2 clone. A total of 18 anticytokine mAb were isolated, comprising 6 anti-CSIF, 1 anti-IL-4, 1 anti-IL-5, and 10 anti-IL-6 mAb. The anti-CSIF mAb were separable into three groups. mAb in groups A and B neutralized and depleted bioactivity, and bound to overlapping but nonidentical subpopulations of CSIF molecules. The 2 mAb in group C did not neutralize CSIF activity, and bound to CSIF molecules not recognized by mAb from groups A or B. A two-site sandwich ELISA for CSIF could be established with the group A antibody, SXC1, combined with any of the three group B antibodies. The sensitivity of this assay was equivalent to that of the CSIF bioassay. These antibodies have been used to show that CSIF is responsible for most or all of the ability of Th2 supernatants to inhibit cytokine synthesis by Th1 cells. In addition, the ELISA has been used to confirm that CSIF is produced by Th2 but not Th1 clones.

Animals↗
PubMed1990

Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI.

Complementary DNA clones encoding mouse cytokine synthesis inhibitory factor (CSIF; interleukin-10), which inhibits cytokine synthesis by TH1 helper T cells, were isolated and expressed. The predicted protein sequence shows extensive homology with an uncharacterized open reading frame, BCRFI, in the Epstein-Barr virus genome, suggesting the possibility that this herpes virus exploits the biological activity of a captured cytokine gene to enhance its survival in the host.

Amino Acid Sequence↗
PubMed1990

Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells.

Many long term mouse Th clones express either the type 1 or type 2 Th cell (Th1 or Th2) cytokine secretion phenotype. In this report we present two lines of evidence for the existence of additional Th differentiation states. Lectin-stimulated spleen cells secreted moderate levels of IL-2 compared with long term Th1 clones, whereas the levels of other cytokines were more than 100-fold lower than those produced by either Th1 or Th2 clones. This suggests that many spleen cells produce substantial amounts of IL-2 but little or no IL-4, IL-5, IFN-gamma, IL-3, and granulocyte/macrophage-CSF. In contrast to long term Th clones, many short term alloreactive clones displayed cytokine secretion phenotypes intermediate between the Th1 and Th2 patterns. The proportion of recognizable Th1 and Th2 clones at early times in culture was greatly increased by immunization of the mice from which the responder and stimulator cells were derived; Brucella abortus immunization resulted in the isolation of exclusively Th1 clones, whereas infection with Nippostrongylus brasiliensis resulted in a strong trend toward the isolation of Th2 clones. The immunization of mice from which responder cells were derived strongly affected the type of Th clone obtained, whereas the source of stimulator cells had much less effect, suggesting that the commitment of Th cells to the Th1 or Th2 phenotypes occurred mainly in vivo. A model for the possible relationships of the various Th cells is presented.

Animals↗
PubMed1990

Alloreactive murine CD8+ T cell clones secrete the Th1 pattern of cytokines.

A large panel of CD8+ mouse T cell clones expressed the cytokine synthesis pattern characteristic of Th1 clones. CD8+ clones synthesized IFN-gamma and lymphotoxin at levels similar to Th1 clones, whereas IL-2 was synthesized by only 50% of the clones and at significantly lower levels compared to Th1 clones. CD8+ clones also produced substantial amounts of granulocyte/macrophage-CSF, TY5, P500, and TNF-alpha which are expressed preferentially by Th1 clones and at lower levels by Th2 clones. The level of IL-3 produced by CD8+ clones was approximately 10% of that produced by Th1 and Th2 clones. Some CD8+ clones expressed low levels of the Th2-preferential product preproenkelphalin. None of the CD8+ clones expressed detectable levels of the Th2-specific products IL-4, IL-5, and P600, and the great majority did not express IL-6. The cytokine profile of CD8+ clones is representative of that secreted by activated normal CD8+ splenocytes, which includes IFN-gamma, low levels of IL-2 and IL-3 but no IL-4 or IL-5. Inasmuch as many Th1/Th2 functions are cytokine mediated, the striking similarity of the Th1 and CD8+ cytokine secretion patterns helps to explain why these two cell types share certain functions such as DTH, and also suggests that further common functions may be discovered in the future.

Animals↗
PubMed1990

Lymphokine control of in vivo immunoglobulin isotype selection.

Several specific conclusions can be drawn from these studies: 1. IL-4 is required for the generation of both primary polyclonal and secondary antigen-specific IgE responses in vivo. 2. IL-4 is required to maintain established, ongoing, antigen-specific and polyclonal IgE responses. 3. Most, but not all, polyclonal IgE production during a secondary immune response is IL-4-dependent. Memory B cells that have already switched to IgE at the DNA level may no longer require stimulation with IL-4 to be induced to secrete IgE. 4. The generation of a secondary IgE response is not dependent upon the presence of IL-4 during primary immunization. However, if IL-4 is not present during primary immunization, it is required during secondary immunization for the generation of an IgE response. 5. IL-4 does not appear to be required for the generation of in vivo IgG1 responses, and in at least some instances, does not contribute significantly to the generation of IgG1 responses in vivo. 6. A late-acting form of T-cell help other than IL-4 appears to be required for the generation of an IgE, but not an IgG1 response. 7. An antibody that inhibits IL-4 binding to IL-4 receptors affects Ig isotype selection in the same way as an antibody that neutralizes IL-4. 8. IFN-gamma can act in both spontaneous and induced immune responses to suppress IgE production. 9. IFN-gamma can also suppress IgG1 production and stimulate IgG2a production. However, IFN-gamma appears to suppress polyclonal IgG1 responses more than antigen-specific IgG1 responses, and it enhances, but is not required for, the generation of IgG2a responses. 10. IFN-alpha appears to resemble IFN-gamma in its ability to inhibit IgE and enhance IgG2a responses in GaM delta-injected mice, but it requires the presence of IFN-gamma to suppress IgG1 production in these mice. 11. Both IFN-alpha and IFN-gamma appear to be able to decrease IgE production in some human patients. 12. There is no direct evidence that IL-5 contributes to the generation of in vivo antibody responses. Two general conclusions may also be drawn.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗