Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

EA Tivol, F Borriello, AN Schweitzer, WP Lynch… - Immunity, 1995 - cell.com
EA Tivol, F Borriello, AN Schweitzer, WP Lynch, JA Bluestone, AH Sharpe
Immunity, 1995cell.com
Summary The B7-CD28/CTLA-4 costlmulatory pathway can provide a signal pivotal for T cell
activation. Signaling through this pathway is complex due to the presence of two 87 family
members, 87-l and 87-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-
CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4
in T ceil activation. To elucidate the in vivo function of CTLA-4, we generated CTLA4-
deficient mice. These mice rap idly develop lymphoproiiferative disease with multiorgan …
Summary
The B7-CD28/CTLA-4 costlmulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two 87 family members, 87-l and 87-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T ceil activation. To elucidate the in vivo function of CTLA-4, we generated CTLA4-deficient mice. These mice rap idly develop lymphoproiiferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditls and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-Gdeflcient mouse strain is supported by studies that have suggested a negative role for CTLA-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 lmmunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.
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