Related Experiment Video
Updated: Jul 20, 2026
Accessing Early Differentiation of Virus-Specific Follicular Helper CD4+ T Cell in Acute LCMV-Infected Mice
Published on: April 26, 2024
Transgenic expression of the viral FLIP MC159 causes lpr/gld-like lymphoproliferation and autoimmunity
Melissa Woelfel1, Jacqueline Bixby, Michael A Brehm
1Department of Pathology, Immunology and Virology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Abstract:
Death receptor-induced programmed cell death (PCD) is crucial for the maintenance of immune homeostasis. However, interference of downstream death receptor signaling by genetic ablation or transgenic (Tg) expression of different apoptosis inhibitors often impairs lymphocyte activation. The viral FLICE (caspase-8)-like inhibitor proteins (v-FLIPs) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. We generated Tg mice expressing the v-FLIP MC159 from Molluscum contagiosum virus under the control of the H2Kb class I MHC promoter to examine the role of death receptor-induced PCD in the control of immune functions and homeostasis. We found that expression of MC159 led to lymphoproliferation and autoimmunity as exemplified by T and B lymphocyte expansion, accumulation of TCRalphabeta+ CD3+ B220+ CD4- CD8- lymphocytes in secondary lymphoid organs, elevated serum Ig levels, and increased anti-dsDNA Ab titers. These phenotypes were caused by defective death receptor-induced apoptosis, but not by defective passive cell death in the absence of mitogenic stimulation. Lymphocyte activation was normal, as demonstrated by normal thymidine incorporation and CSFE dilution of T cells stimulated with anti-CD3 and anti-CD28 Abs. In addition, effector CD8+ T cell responses to acute and memory lymphocytic choriomeningitis virus infections were unaffected in the Tg mice. These phenotypes are reminiscent of the lpr and gld mice, and show that the v-FLIP MC159 is a bona fide PCD inhibitor that does not interfere with other essential lymphocyte functions. Thus, the MC159-Tg mice provide a model to study the effects of PCD in immune responses without hampering other important lymphocyte functions.
Insights
Viral inhibitors of programmed cell death (PCD) can cause autoimmunity. Transgenic mice expressing v-FLIP MC159 developed lymphoproliferation and autoimmunity due to impaired PCD, but maintained normal lymphocyte activation and immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Programmed cell death (PCD) is vital for immune homeostasis.
- Inhibiting death receptor signaling can impair lymphocyte function.
- Viral FLICE (caspase-8)-like inhibitor proteins (v-FLIPs) block apoptosis and programmed necrosis.
Purpose of the Study:
- To investigate the role of death receptor-induced PCD in immune control.
- To generate transgenic mice expressing the v-FLIP MC159 to study PCD inhibition.
- To assess the impact of v-FLIP MC159 on lymphocyte function and autoimmunity.
Main Methods:
- Generation of transgenic mice expressing v-FLIP MC159 under the H2Kb promoter.
- Analysis of lymphocyte populations, serum immunoglobulin levels, and autoantibodies.
- Assessment of T cell activation via thymidine incorporation and CFSE dilution.
- Evaluation of CD8+ T cell responses to viral infections.
Main Results:
- MC159 transgenic mice exhibited lymphoproliferation and autoimmunity, including lymphocyte expansion and increased autoantibodies.
- Phenotypes resulted from defective death receptor-induced apoptosis, not passive cell death.
- Lymphocyte activation and effector CD8+ T cell responses to viral infections remained normal.
- v-FLIP MC159 inhibited PCD without compromising other lymphocyte functions.
Conclusions:
- v-FLIP MC159 acts as a potent inhibitor of PCD.
- MC159 transgenic mice serve as a valuable model for studying PCD's role in immunity.
- PCD inhibition can lead to autoimmunity while preserving other immune functions.
