Heterozygous Ctla4tm1All mice are viable, fertile, and normal in size and exhibit diabetes incidence comparable to NOD.
Ctla4tm1All homozygous mice on various backgrounds, including C57BL/6, BALB/c, 129 and NOD, die at 3-4 weeks of age due to massive polyclonal expansion of T-cells and massive lymphocyte infiltration into non-lymphoid organs, such as heart, liver, lung and pancreas. Treatment with murine Ctla4Ig or depletion of CD4+ T-cells blocks this lymphoproliferative disease. Splenic and lymph node T-cells display an activated phenotype characterized as CD69+, CD25+, CD44hi, Mel14lo, CD45RBlo and Sca1hi and have down regulated the TCR. Lymph node and spleen cells cultured from Ctla4tm1All homozygous mice spontaneously proliferate while wild-type controls do not. Cells from whole lymph nodes or purified T-cells are unresponsive to anti CD28mAb stimulation, while rIl2 increases the proliferative response. Homozygous Ctla4tm1All NOD mice also transgenically expressing the BDC2.5 alpha and beta TCR chains do not exhibit the lymphoproliferative phenotype. Other TCR transgenes exert a similar effect on differing backgrounds. However, all of the mice develop aggressive autoimmunity and rapidly develop diabetes by7 weeks of age.In contrast, mice heterozygous for Ctla4tm1All and transgenically expressing the BDC2.5 TCR have late and relatively rare diabetes.
NOD.129(B6)-Ctla4tm1All/DoiJ may be useful for studying the role of Ctla4/Cd28:Cd80/Cd86 in the regulation of self tolerance and susceptibility to autoimmune diseases.
