Two programmed cell death pathways, apoptosis and necrosis, impact T cell function in mice and humans. Germ line disruption of pro-apoptotic caspase 8 (Casp8) activity in T cells triggers receptor interacting protein kinase (RIP)3-dependent necrosis upon TCR stimulation. This absolute requirement for Casp8 repression of RIP3-dependent pathways overshadows potential contributions of extrinsic apoptosis to T cell expansion and contraction. Mice deficient in both Casp8 and RIP3 (Casp8-/-Rip3-/-) have an intact immune compartment and maintain naïve CD8 T cells comparable to Rip3-/- and WT controls. Based on CD44 expression, aging mice show evidence of CD8 T cell proliferation and lymphadenopathy. Despite this, CD8 T cells in Casp8-/-Rip3-/- mice proliferate normally in response to TCR stimulation. Upon infection with murine CMV, Ag-specific CD8 T cells from Casp8-/-Rip3-/- mice expand, produce cytokines, kill cells expressing viral peptide, and control infection similarly to controls. Memory CD8 T cells develop in Casp8-/-Rip3-/- mice with appropriate KLRG1 and CD127 expression. These memory cells expand in response to and protect from secondary challenge. Additionally, memory inflation, a characteristic of the response to murine CMV, is preserved. Thus, when RIP3 pathways are eliminated, Casp8 restricts homeostatic lymphoproliferation but plays no direct role in the CD8 T cell response to infection.
- Copyright © 2013 by The American Association of Immunologists, Inc.