LOSS OF CTLA-4 LEADS TO MASSIVE LYMPHOPROLIFERATION AND FATAL MULTIORGAN TISSUE DESTRUCTION, REVEALING A CRITICAL NEGATIVE REGULATORY ROLE OF CTLA-4

The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation, Signaling through this pathway is complex due t o the presence of two B7 family members, B7-1 and B7-2, and two counte rreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antib odies have suggested both positive and negative roles for CTLA-4 in T cell activation, To elucidate the in vivo function of CTLA-4, we gener ated CTLA-4-deficient mice. These mice rapidly develop lymphoprolifera tive disease with multiorgan lymphocytic infiltration and tissue destr uction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse stra in is supported by studies that have suggested a negative role for CTL A-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in downregulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, pe ripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.