MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4)

William Stohl, Dong Xu, Kyoung Soo Kim, Chella S. David, James P. Allison

Research output: Contribution to journalArticle

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Abstract

One of the key downregulators of T cell activation is CD152 (CTLA-4). Mice genetically deficient in CD152 (cd152-/- mice) develop massive expansion of both CD4+ and CD8+ T cells as well as increased numbers of splenic Ig-secreting cells and serum Ig levels. To determine the dependence of the lymphoproliferation and B cell hyperactivity on MHC class II (MHCII), MHCII-deficient (mhcii-/-) cd152-/- mice were generated. Compared to that in their mhcii+/+ counterparts, expansion of CD4+ cells in mhcii-/-cd152-/- mice was markedly attenuated. Nonetheless, expansion of CD8+ cells was identical in both sets of mice, demonstrating that the effects of CD152 deficiency on CD4+ cells can quantitatively be dissociated from those on CD8+ cells, and pointing to a critical downregulatory role for CD152 in MHCII-independent CD8+ cell activation in vivo. B cell hyperactivity also developed in mhcii-/-cd152-/- mice, albeit in a manner less rapid and less intense than that in their mhcii+/+ counterparts, demonstrating an underlying MHCII-Independent diathesis to B cell dysregulation and pointing to a critical downregulatory role for CD152 in MHCII-independent B cell activation in vivo. When human DQ8 was introduced as a transgene into mhcii-/-cd152-/- mice, B cell hyperactivity was restored to levels observed in mhcii+/+cd152-/- mice, pointing to a critical downregulatory role for CD152 in MHCII-dependent B cell activation in vivo superimposed upon its downregulatory role on MHCII-independent B cell activation.

Original languageEnglish (US)
Pages (from-to)895-904
Number of pages10
JournalInternational Immunology
Volume16
Issue number7
DOIs
StatePublished - Jul 2004

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B-Lymphocytes
T-Lymphocytes
Disease Susceptibility
Transgenes
Serum

Keywords

  • CD4 cells
  • CD8 cells
  • Ig-secreting cells
  • IgG
  • IgM

ASJC Scopus subject areas

  • Immunology

Cite this

MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4). / Stohl, William; Xu, Dong; Kim, Kyoung Soo; David, Chella S.; Allison, James P.

In: International Immunology, Vol. 16, No. 7, 07.2004, p. 895-904.

Research output: Contribution to journalArticle

Stohl, William ; Xu, Dong ; Kim, Kyoung Soo ; David, Chella S. ; Allison, James P. / MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4). In: International Immunology. 2004 ; Vol. 16, No. 7. pp. 895-904.
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AB - One of the key downregulators of T cell activation is CD152 (CTLA-4). Mice genetically deficient in CD152 (cd152-/- mice) develop massive expansion of both CD4+ and CD8+ T cells as well as increased numbers of splenic Ig-secreting cells and serum Ig levels. To determine the dependence of the lymphoproliferation and B cell hyperactivity on MHC class II (MHCII), MHCII-deficient (mhcii-/-) cd152-/- mice were generated. Compared to that in their mhcii+/+ counterparts, expansion of CD4+ cells in mhcii-/-cd152-/- mice was markedly attenuated. Nonetheless, expansion of CD8+ cells was identical in both sets of mice, demonstrating that the effects of CD152 deficiency on CD4+ cells can quantitatively be dissociated from those on CD8+ cells, and pointing to a critical downregulatory role for CD152 in MHCII-independent CD8+ cell activation in vivo. B cell hyperactivity also developed in mhcii-/-cd152-/- mice, albeit in a manner less rapid and less intense than that in their mhcii+/+ counterparts, demonstrating an underlying MHCII-Independent diathesis to B cell dysregulation and pointing to a critical downregulatory role for CD152 in MHCII-independent B cell activation in vivo. When human DQ8 was introduced as a transgene into mhcii-/-cd152-/- mice, B cell hyperactivity was restored to levels observed in mhcii+/+cd152-/- mice, pointing to a critical downregulatory role for CD152 in MHCII-dependent B cell activation in vivo superimposed upon its downregulatory role on MHCII-independent B cell activation.

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