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Impairment of T and B cell development by treatment with a type I interferon.

Lin Q, Dong C, Cooper MD - J. Exp. Med. (1998)

Bottom Line: Correspondingly, IL-7-responsive cells in the bone marrow were virtually eliminated by the interferon treatment.Phenotypic analysis of the residual thymocytes indicated that the inhibitory effect was exerted during the pro-T cell stage in differentiation.The data suggest that type I interferons can reversibly inhibit early T and B cell development by opposing the essential IL-7 response.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
Type I interferons alpha and beta, naturally produced regulators of cell growth and differentiation, have been shown to inhibit IL-7-induced growth and survival of B cell precursors in vitro. After confirming an inhibitory effect on B lymphopoiesis in an ex vivo assay, we treated newborn mice with an active IFN-alpha2/alpha1 hybrid molecule to assess its potential for regulating B and T cell development in vivo. Bone marrow and splenic cellularity was greatly reduced in the IFN-alpha2/alpha1-treated mice, and B lineage cells were reduced by >80%. The bone marrow progenitor population of CD43+B220+HSA- cells was unaffected, but development of the CD19+ pro-B cells and their B lineage progeny was severely impaired. Correspondingly, IL-7-responsive cells in the bone marrow were virtually eliminated by the interferon treatment. Thymus cellularity was also reduced by >80% in the treated mice. Phenotypic analysis of the residual thymocytes indicated that the inhibitory effect was exerted during the pro-T cell stage in differentiation. In IFN-alpha/beta receptor-/- mice, T and B cell development were unaffected by the IFN-alpha2/alpha1 treatment. The data suggest that type I interferons can reversibly inhibit early T and B cell development by opposing the essential IL-7 response.

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Immunofluorescence profile analysis of thymocyte subpopulations from PBS- and IFN-α2/α1–treated mice. Cells were stained with  anti-CD4, anti-CD8, anti-CD44, and anti-CD25 antibodies. Percentages  of cells within each quadrant are indicated. (A) Analysis of the total thymocyte population for CD4 and CD8 expression; (B) CD25 and CD44  expression by the CD4−CD8− thymocyte subpopulation, and (C) DX5  expression by the CD44+CD25− subpopulation of the CD4−CD8− thymocytes.
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Figure 6: Immunofluorescence profile analysis of thymocyte subpopulations from PBS- and IFN-α2/α1–treated mice. Cells were stained with anti-CD4, anti-CD8, anti-CD44, and anti-CD25 antibodies. Percentages of cells within each quadrant are indicated. (A) Analysis of the total thymocyte population for CD4 and CD8 expression; (B) CD25 and CD44 expression by the CD4−CD8− thymocyte subpopulation, and (C) DX5 expression by the CD44+CD25− subpopulation of the CD4−CD8− thymocytes.

Mentions: Thymic cellularity was reduced by >85% in IFN-α2/α1– treated mice (Table 1). When IFN-α2/α1 effects on the different thymocyte subpopulations were evaluated by determining the CD4 and CD8 expression, a 50% decrease in the percentage of CD4+CD8+ thymocytes was observed, whereas the relative proportions of CD4+CD8− and CD4−CD8+ thymocytes were increased (Fig. 6 A). To determine more precisely where IFN-α2/α1 inhibited the progression of thymocyte differentiation, we examined the differential expression of CD44 and CD25, cell surface markers that serve to discriminate the CD4−CD8− subpopulations of thymocyte progenitors (15, 16). In this analysis, an increased percentage of the relatively immature CD44+CD25− cells was observed along with a decreased percentage of the more mature CD44−CD25− cells within the CD4−CD8− thymocyte population in IFN-α2/α1–treated mice (Fig. 6 B). The early CD44+CD25− population of thymocytes contains precursors for T cells, NK cells, and dendritic cells (39–41), and the increased frequency of CD44+CD25− cells in the thymus of IL-7−/− mice could in part reflect an increased frequency of NK cells (42). When the CD44+CD25− cells from IFN-treated mice were examined, a twofold increase was indeed observed in the percentage of DX5+ cells (Fig. 6 C). Thus, the composite data indicate that the IFN-α2/ α1 inhibition of T cell development begins at an early progenitor stage.


Impairment of T and B cell development by treatment with a type I interferon.

Lin Q, Dong C, Cooper MD - J. Exp. Med. (1998)

Immunofluorescence profile analysis of thymocyte subpopulations from PBS- and IFN-α2/α1–treated mice. Cells were stained with  anti-CD4, anti-CD8, anti-CD44, and anti-CD25 antibodies. Percentages  of cells within each quadrant are indicated. (A) Analysis of the total thymocyte population for CD4 and CD8 expression; (B) CD25 and CD44  expression by the CD4−CD8− thymocyte subpopulation, and (C) DX5  expression by the CD44+CD25− subpopulation of the CD4−CD8− thymocytes.
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Related In: Results  -  Collection

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Figure 6: Immunofluorescence profile analysis of thymocyte subpopulations from PBS- and IFN-α2/α1–treated mice. Cells were stained with anti-CD4, anti-CD8, anti-CD44, and anti-CD25 antibodies. Percentages of cells within each quadrant are indicated. (A) Analysis of the total thymocyte population for CD4 and CD8 expression; (B) CD25 and CD44 expression by the CD4−CD8− thymocyte subpopulation, and (C) DX5 expression by the CD44+CD25− subpopulation of the CD4−CD8− thymocytes.
Mentions: Thymic cellularity was reduced by >85% in IFN-α2/α1– treated mice (Table 1). When IFN-α2/α1 effects on the different thymocyte subpopulations were evaluated by determining the CD4 and CD8 expression, a 50% decrease in the percentage of CD4+CD8+ thymocytes was observed, whereas the relative proportions of CD4+CD8− and CD4−CD8+ thymocytes were increased (Fig. 6 A). To determine more precisely where IFN-α2/α1 inhibited the progression of thymocyte differentiation, we examined the differential expression of CD44 and CD25, cell surface markers that serve to discriminate the CD4−CD8− subpopulations of thymocyte progenitors (15, 16). In this analysis, an increased percentage of the relatively immature CD44+CD25− cells was observed along with a decreased percentage of the more mature CD44−CD25− cells within the CD4−CD8− thymocyte population in IFN-α2/α1–treated mice (Fig. 6 B). The early CD44+CD25− population of thymocytes contains precursors for T cells, NK cells, and dendritic cells (39–41), and the increased frequency of CD44+CD25− cells in the thymus of IL-7−/− mice could in part reflect an increased frequency of NK cells (42). When the CD44+CD25− cells from IFN-treated mice were examined, a twofold increase was indeed observed in the percentage of DX5+ cells (Fig. 6 C). Thus, the composite data indicate that the IFN-α2/ α1 inhibition of T cell development begins at an early progenitor stage.

Bottom Line: Correspondingly, IL-7-responsive cells in the bone marrow were virtually eliminated by the interferon treatment.Phenotypic analysis of the residual thymocytes indicated that the inhibitory effect was exerted during the pro-T cell stage in differentiation.The data suggest that type I interferons can reversibly inhibit early T and B cell development by opposing the essential IL-7 response.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
Type I interferons alpha and beta, naturally produced regulators of cell growth and differentiation, have been shown to inhibit IL-7-induced growth and survival of B cell precursors in vitro. After confirming an inhibitory effect on B lymphopoiesis in an ex vivo assay, we treated newborn mice with an active IFN-alpha2/alpha1 hybrid molecule to assess its potential for regulating B and T cell development in vivo. Bone marrow and splenic cellularity was greatly reduced in the IFN-alpha2/alpha1-treated mice, and B lineage cells were reduced by >80%. The bone marrow progenitor population of CD43+B220+HSA- cells was unaffected, but development of the CD19+ pro-B cells and their B lineage progeny was severely impaired. Correspondingly, IL-7-responsive cells in the bone marrow were virtually eliminated by the interferon treatment. Thymus cellularity was also reduced by >80% in the treated mice. Phenotypic analysis of the residual thymocytes indicated that the inhibitory effect was exerted during the pro-T cell stage in differentiation. In IFN-alpha/beta receptor-/- mice, T and B cell development were unaffected by the IFN-alpha2/alpha1 treatment. The data suggest that type I interferons can reversibly inhibit early T and B cell development by opposing the essential IL-7 response.

Show MeSH
Related in: MedlinePlus