Limits...
Selective expression of an interleukin-12 receptor component by human T helper 1 cells.

Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F - J. Exp. Med. (1997)

Bottom Line: Here we show that the IL-12 receptor (IL-12R) beta 2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway.IL-12 and type I but not type II interferons induce expression of the IL-12R beta 2 chain during in vitro T cell differentiation after antigen receptor triggering.The selective expression and regulation of the IL-12R beta 2 subunit may help to understand the basis of Th1/Th2 differentiation and may provide therapeutic options for altering the Th1/Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies.

View Article: PubMed Central - PubMed

Affiliation: Roche Milano Ricerche, Italy.

ABSTRACT
Interleukin-12 (IL-12), a heterodimeric cytokine produced by activated monocytes and dendritic cells, plays a crucial role in regulating interferon (IFN)-gamma production and in the generation of IFN-gamma-producing T helper 1 (Th1) cells. Here we show that the IL-12 receptor (IL-12R) beta 2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway. IL-12 and type I but not type II interferons induce expression of the IL-12R beta 2 chain during in vitro T cell differentiation after antigen receptor triggering. The selective expression and regulation of the IL-12R beta 2 subunit may help to understand the basis of Th1/Th2 differentiation and may provide therapeutic options for altering the Th1/Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies.

Show MeSH

Related in: MedlinePlus

Function of type I and II IFNs in the development of T  helper cell subsets and on the expression of the IL-12R β2 subunit. (A)  IFN-α induces Th1 development. T cell lines were generated by stimulating cord blood lymphocytes with PHA in the presence of the indicated  cytokines or anti-cytokine antibodies. IFN-α or IFN-γ (1,000 U/ml)  were added at the time of priming to the cultures as indicated. Cytokine  production was determined on day 10. IFN-α, but not IFN-γ, induces a  Th1 phenotype even in the presence of IL-4 and neutralizing anti–IL-12  antibodies. (B) IFN-α induced Th1 cells express IL-12R β2 transcripts.  RNA was extracted from T cell lines 10 d after priming in the presence of  the indicated cytokines or neutralizing anti-cytokine antibodies. RNase  protection assays were performed as described above. (C) IFN-α induced  Th1 cells are IL-12 responsive. T cell lines (Fig. 6 A) were harvested on  day 10 after priming. 8 × 106 cells were washed and incubated 15 min at  37°C in medium with or without 2 ng/ml IL-12 in 1 ml RPMI-FCS.  IL-12 induced Stat4 phosphorylation was determined as described above.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196163&req=5

Figure 6: Function of type I and II IFNs in the development of T helper cell subsets and on the expression of the IL-12R β2 subunit. (A) IFN-α induces Th1 development. T cell lines were generated by stimulating cord blood lymphocytes with PHA in the presence of the indicated cytokines or anti-cytokine antibodies. IFN-α or IFN-γ (1,000 U/ml) were added at the time of priming to the cultures as indicated. Cytokine production was determined on day 10. IFN-α, but not IFN-γ, induces a Th1 phenotype even in the presence of IL-4 and neutralizing anti–IL-12 antibodies. (B) IFN-α induced Th1 cells express IL-12R β2 transcripts. RNA was extracted from T cell lines 10 d after priming in the presence of the indicated cytokines or neutralizing anti-cytokine antibodies. RNase protection assays were performed as described above. (C) IFN-α induced Th1 cells are IL-12 responsive. T cell lines (Fig. 6 A) were harvested on day 10 after priming. 8 × 106 cells were washed and incubated 15 min at 37°C in medium with or without 2 ng/ml IL-12 in 1 ml RPMI-FCS. IL-12 induced Stat4 phosphorylation was determined as described above.

Mentions: In the mouse, IL-4 has been shown to block the development of naive CD4+ T cells into Th1 effectors. The block is complete if IL-12 is not present in the priming culture, but incomplete if IL-12 is present (9). Consistent with this observation, we found that cord blood lymphocytes primed in the presence of IL-4 and IL-12 together developed into cells secreting both IL-4 (1.1 ng/ml) and IFN-γ (0.9 ng/ml) (Fig. 6 A). These cells phosphorylate Stat4 in response to IL-12 and accordingly express the IL-12R β2 mRNA, although to a lower level, as compared to Th1 cells (Fig. 6, B and C). In contrast, neonatal cells primed in the presence of IL-4 and neutralizing anti–IL-12 mAb completely lost IL-12R β2 expression (Figs. 3 A and 6 B) and consequently, IL-12–mediated signaling (Figs. 2 and 6 C). Although the mechanism by which IL-4 induces the generation of IL-12 nonresponsive Th2 cells remains to be clarified, our results are consistent with a model in which IL-12 prevents the gradual extinction of the IL-12R β2 subunit that appears to follow exposure to IL-4. Alternatively, the presence of IL-12 or IL-4 could result in the preferential expansion of IL-12 responsive Th1 cells or IL-12 nonresponsive Th2 cells, respectively.


Selective expression of an interleukin-12 receptor component by human T helper 1 cells.

Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F - J. Exp. Med. (1997)

Function of type I and II IFNs in the development of T  helper cell subsets and on the expression of the IL-12R β2 subunit. (A)  IFN-α induces Th1 development. T cell lines were generated by stimulating cord blood lymphocytes with PHA in the presence of the indicated  cytokines or anti-cytokine antibodies. IFN-α or IFN-γ (1,000 U/ml)  were added at the time of priming to the cultures as indicated. Cytokine  production was determined on day 10. IFN-α, but not IFN-γ, induces a  Th1 phenotype even in the presence of IL-4 and neutralizing anti–IL-12  antibodies. (B) IFN-α induced Th1 cells express IL-12R β2 transcripts.  RNA was extracted from T cell lines 10 d after priming in the presence of  the indicated cytokines or neutralizing anti-cytokine antibodies. RNase  protection assays were performed as described above. (C) IFN-α induced  Th1 cells are IL-12 responsive. T cell lines (Fig. 6 A) were harvested on  day 10 after priming. 8 × 106 cells were washed and incubated 15 min at  37°C in medium with or without 2 ng/ml IL-12 in 1 ml RPMI-FCS.  IL-12 induced Stat4 phosphorylation was determined as described above.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196163&req=5

Figure 6: Function of type I and II IFNs in the development of T helper cell subsets and on the expression of the IL-12R β2 subunit. (A) IFN-α induces Th1 development. T cell lines were generated by stimulating cord blood lymphocytes with PHA in the presence of the indicated cytokines or anti-cytokine antibodies. IFN-α or IFN-γ (1,000 U/ml) were added at the time of priming to the cultures as indicated. Cytokine production was determined on day 10. IFN-α, but not IFN-γ, induces a Th1 phenotype even in the presence of IL-4 and neutralizing anti–IL-12 antibodies. (B) IFN-α induced Th1 cells express IL-12R β2 transcripts. RNA was extracted from T cell lines 10 d after priming in the presence of the indicated cytokines or neutralizing anti-cytokine antibodies. RNase protection assays were performed as described above. (C) IFN-α induced Th1 cells are IL-12 responsive. T cell lines (Fig. 6 A) were harvested on day 10 after priming. 8 × 106 cells were washed and incubated 15 min at 37°C in medium with or without 2 ng/ml IL-12 in 1 ml RPMI-FCS. IL-12 induced Stat4 phosphorylation was determined as described above.
Mentions: In the mouse, IL-4 has been shown to block the development of naive CD4+ T cells into Th1 effectors. The block is complete if IL-12 is not present in the priming culture, but incomplete if IL-12 is present (9). Consistent with this observation, we found that cord blood lymphocytes primed in the presence of IL-4 and IL-12 together developed into cells secreting both IL-4 (1.1 ng/ml) and IFN-γ (0.9 ng/ml) (Fig. 6 A). These cells phosphorylate Stat4 in response to IL-12 and accordingly express the IL-12R β2 mRNA, although to a lower level, as compared to Th1 cells (Fig. 6, B and C). In contrast, neonatal cells primed in the presence of IL-4 and neutralizing anti–IL-12 mAb completely lost IL-12R β2 expression (Figs. 3 A and 6 B) and consequently, IL-12–mediated signaling (Figs. 2 and 6 C). Although the mechanism by which IL-4 induces the generation of IL-12 nonresponsive Th2 cells remains to be clarified, our results are consistent with a model in which IL-12 prevents the gradual extinction of the IL-12R β2 subunit that appears to follow exposure to IL-4. Alternatively, the presence of IL-12 or IL-4 could result in the preferential expansion of IL-12 responsive Th1 cells or IL-12 nonresponsive Th2 cells, respectively.

Bottom Line: Here we show that the IL-12 receptor (IL-12R) beta 2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway.IL-12 and type I but not type II interferons induce expression of the IL-12R beta 2 chain during in vitro T cell differentiation after antigen receptor triggering.The selective expression and regulation of the IL-12R beta 2 subunit may help to understand the basis of Th1/Th2 differentiation and may provide therapeutic options for altering the Th1/Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies.

View Article: PubMed Central - PubMed

Affiliation: Roche Milano Ricerche, Italy.

ABSTRACT
Interleukin-12 (IL-12), a heterodimeric cytokine produced by activated monocytes and dendritic cells, plays a crucial role in regulating interferon (IFN)-gamma production and in the generation of IFN-gamma-producing T helper 1 (Th1) cells. Here we show that the IL-12 receptor (IL-12R) beta 2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway. IL-12 and type I but not type II interferons induce expression of the IL-12R beta 2 chain during in vitro T cell differentiation after antigen receptor triggering. The selective expression and regulation of the IL-12R beta 2 subunit may help to understand the basis of Th1/Th2 differentiation and may provide therapeutic options for altering the Th1/Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies.

Show MeSH
Related in: MedlinePlus