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

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.