International Immunology Advance Access originally published online on May 10, 2004
International Immunology 2004 16(7):895-904; doi:10.1093/intimm/dxh091
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International Immunology, Vol. 16, No. 7, pp. 895-904,
July 2004
© 2004 Japanese Society for Immunology
MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4)
Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, 1 Department of Immunology, Mayo Clinic, Rochester, MN 55905 and 2 Cancer Research Laboratory, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA
Correspondence to: W. Stohl; E-mail: stohl{at}usc.edu
Transmitting editor: T. Tedder
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.
Keywords: CD4+ cells; CD8+ cells; IgG; IgM; Ig-secreting cells
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