Unlike CTLA-4 germline knockout CTLA-4−/− mice, which spontaneously and rapidly developed fatal lymphoproliferative disease with massive expansion of activated T cells (146, 147), PD-1−/− mice with different genetic backgrounds slowly developed lupus-like proliferative arthritis, glomerulonephritis, splenomegaly, or dilated cardiomyopathy with high-titer autoantibodies in early PD-1 studies (148–150), suggesting that PD-1 can inhibit B cell proliferation and differentiation. Here, CTLA4 is linked to Splenomegaly.