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IL-2 reverses human T-cell unresponsiveness induced by thymic epithelium in SCID-HU mice

(1994) JOURNAL OF IMMUNOLOGY. 152(5). p.2198-2206
Author
Organization
Abstract
In this study we investigated the mechanism responsible for the unresponsiveness of thymus-reactive T cells obtained from severe combined immunodeficient (SCID) mice constructed with human fetal liver (FL) stem cells from donor A and an allogeneic human fetal thymus (FT) from donor B (A/B SCID-hu mice). These A/B SCID-hu mice have a human thymus containing B cells, macrophages, and dendritic cells from FL donor A but thymic epithelial cells from FT donor B. The repertoire of human T cells developing in this chimeric thymus is depleted of T cells specific for the HLA Ags of the FL donor, whereas T cells reactive against the HLA Ags expressed by the FT donor are still present. However, these thymocytes failed to proliferate and expressed low levels of the activation markers CD25, CD71, and HLA-DR after stimulation with the EBV-LCL of the FT donor in primary MLRs. This unresponsiveness could be completely reversed by IL-2. Restoration of T cell responsiveness was Ag specific and a unique property of IL-2. The T cells produced very low levels of IL-2 when stimulated with the HLA Ags of FT donor B, whereas they secreted normal levels of IL-2 after activation by third party alloantigens. Low IL-2 production was also observed at the clonal level. CD4(+) T cell clones from A/B SCID-hu mice, specific for the HLA Ags of B, produced significantly less IL-2 and granulocyte macrophage-CSF than control CD4(+) T cell clones. However, these T cell clones synthesized normal levels of IL-2 and granulocyte macrophage-CSF after stimulation with combinations of PMA/Calo or PMA/anti-CD3 mAb. Thus, T cells that differentiate in a chimeric thymus containing allogeneic host thymic epithelium are rendered tolerant to the HLA Ags expressed by the thymic epithelial cells. This tolerance results in the presence of T cells that do not proliferate properly after Ag-specific stimulation. This lack of proliferation is primarily related to their inability to produce sufficient levels of IL-2 and can be restored by exogenous IL-2.
Keywords
ANTIGENS, CHIMERA, INDUCTION, REACTIVITY, LYMPHOCYTES, GROWTH, INTERLEUKIN-2, MOUSE, CLONAL ANERGY, TOLERANCE

Citation

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MLA
Schols, D et al. “IL-2 Reverses Human T-cell Unresponsiveness Induced by Thymic Epithelium in SCID-HU Mice.” JOURNAL OF IMMUNOLOGY 152.5 (1994): 2198–2206. Print.
APA
Schols, D., Vandekerckhove, B., Jones, D., & Roncarolo, M. (1994). IL-2 reverses human T-cell unresponsiveness induced by thymic epithelium in SCID-HU mice. JOURNAL OF IMMUNOLOGY, 152(5), 2198–2206.
Chicago author-date
Schols, D, Bart Vandekerckhove, D Jones, and M Roncarolo. 1994. “IL-2 Reverses Human T-cell Unresponsiveness Induced by Thymic Epithelium in SCID-HU Mice.” Journal of Immunology 152 (5): 2198–2206.
Chicago author-date (all authors)
Schols, D, Bart Vandekerckhove, D Jones, and M Roncarolo. 1994. “IL-2 Reverses Human T-cell Unresponsiveness Induced by Thymic Epithelium in SCID-HU Mice.” Journal of Immunology 152 (5): 2198–2206.
Vancouver
1.
Schols D, Vandekerckhove B, Jones D, Roncarolo M. IL-2 reverses human T-cell unresponsiveness induced by thymic epithelium in SCID-HU mice. JOURNAL OF IMMUNOLOGY. 1994;152(5):2198–206.
IEEE
[1]
D. Schols, B. Vandekerckhove, D. Jones, and M. Roncarolo, “IL-2 reverses human T-cell unresponsiveness induced by thymic epithelium in SCID-HU mice,” JOURNAL OF IMMUNOLOGY, vol. 152, no. 5, pp. 2198–2206, 1994.
@article{627378,
  abstract     = {In this study we investigated the mechanism responsible for the unresponsiveness of thymus-reactive T cells obtained from severe combined immunodeficient (SCID) mice constructed with human fetal liver (FL) stem cells from donor A and an allogeneic human fetal thymus (FT) from donor B (A/B SCID-hu mice). These A/B SCID-hu mice have a human thymus containing B cells, macrophages, and dendritic cells from FL donor A but thymic epithelial cells from FT donor B. The repertoire of human T cells developing in this chimeric thymus is depleted of T cells specific for the HLA Ags of the FL donor, whereas T cells reactive against the HLA Ags expressed by the FT donor are still present. However, these thymocytes failed to proliferate and expressed low levels of the activation markers CD25, CD71, and HLA-DR after stimulation with the EBV-LCL of the FT donor in primary MLRs. This unresponsiveness could be completely reversed by IL-2. Restoration of T cell responsiveness was Ag specific and a unique property of IL-2. The T cells produced very low levels of IL-2 when stimulated with the HLA Ags of FT donor B, whereas they secreted normal levels of IL-2 after activation by third party alloantigens. Low IL-2 production was also observed at the clonal level. CD4(+) T cell clones from A/B SCID-hu mice, specific for the HLA Ags of B, produced significantly less IL-2 and granulocyte macrophage-CSF than control CD4(+) T cell clones. However, these T cell clones synthesized normal levels of IL-2 and granulocyte macrophage-CSF after stimulation with combinations of PMA/Calo or PMA/anti-CD3 mAb. Thus, T cells that differentiate in a chimeric thymus containing allogeneic host thymic epithelium are rendered tolerant to the HLA Ags expressed by the thymic epithelial cells. This tolerance results in the presence of T cells that do not proliferate properly after Ag-specific stimulation. This lack of proliferation is primarily related to their inability to produce sufficient levels of IL-2 and can be restored by exogenous IL-2.},
  author       = {Schols, D and Vandekerckhove, Bart and Jones, D and Roncarolo, M},
  issn         = {0022-1767},
  journal      = {JOURNAL OF IMMUNOLOGY},
  keywords     = {ANTIGENS,CHIMERA,INDUCTION,REACTIVITY,LYMPHOCYTES,GROWTH,INTERLEUKIN-2,MOUSE,CLONAL ANERGY,TOLERANCE},
  language     = {eng},
  number       = {5},
  pages        = {2198--2206},
  title        = {IL-2 reverses human T-cell unresponsiveness induced by thymic epithelium in SCID-HU mice},
  volume       = {152},
  year         = {1994},
}