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.