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

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.