Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells

CTLA-4 plays a critical role in regulating T cell activation. CTLA-4-deficient animals develop a fatal lymphoproliferative disorder, characterized by polyclonal expansion of peripheral lymphocytes (Waterhouse etal 1995, Tivol etal 1995. Chambers, etal 1997). The cellular mechanism(s) responsible for the spontaneous T cell activation in these animals has not been determined. Examination of the expression of activation/memory antigens and the incorporation of thymidine analog bromo- deoxyuridine, demonstrated that there is a preferential, CD28- dependent activation/expansion of CD4⁺ T cells in CTLA-4^-/- mice. This results in a skewing of the CD4/CD8 ratio. In vivo antibody depletion of CD8⁺ T cells from birth did not alter the onset or severity of the lympho- proliferative disorder. Conversely, CD4⁺ T cell- depletion prevented the lymphoproliferative disorder. Moreover, the CD8⁺ T cells in these animals maintained a naive, resting phenotype. These results demonstrate that peripheral CD4⁺ T cells initiate the phenotype observed in CTLA-4^-/- mice. In addition these results suggest that the role of CTLA-4 in maintaining T cell homeostasis differs in CD4⁺ compared to CD8⁺ peripheral T cells.