Related Experiment Videos
Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses
R Khattri1, J A Auger, M D Griffin
1Committee on Immunology, Ben May Institute for Cancer Research, Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Abstract:
Mice lacking CTLA-4 die at an age of 2-3 wk due to massive lymphoproliferation, leading to lymphocytic infiltration and destruction of major organs. The onset of the lymphoproliferative disease can be delayed by treatment with murine CTLA4Ig (mCTLA4Ig), starting day 12 after birth. In this study, we have characterized the T cells present in CTLA-4-deficient mice before and after mCTLA4Ig treatment. The T cells present in CTLA-4-deficient mice express the activation markers, CD69 and IL-2R; down-regulate the lymphoid homing receptor, CD62L; proliferate spontaneously in vitro and cannot be costimulated with anti-CD28 mAb consistent with a hyperactivated state. The T cells from CTLA-4-deficient mice survive longer in culture correlating with higher expression of the survival factor, Bcl-xL, in these cells. Most significantly, the CD4+ T cell subset present in CTLA-4-deficient mice secretes high levels of IL-4 and IL-5 upon TCR activation. Treatment of CTLA-4-deficient mice treated with mCTLA4Ig reverses the activation and hyperproliferative phenotype of the CTLA-4-deficient T cells and restores the costimulatory activity of anti-CD28 mAb. Furthermore, T cells from mCTLA4Ig-treated mice are not skewed toward a Th2 cytokine phenotype. Thus, CTLA-4 regulates CD28-dependent peripheral activation of CD4+ T cells. This process results in apoptosis-resistant, CD4+ T cells with a predominantly Th2 phenotype that may be involved in the lethal phenotype in these animals.
Insights
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) deficiency causes lethal lymphoproliferation in mice. Treatment with CTLA4Ig delays this by restoring T-cell function and preventing Th2 skewing.
Area of Science:
- Immunology
- T-cell Biology
- Autoimmunity
Background:
- Mice lacking CTLA-4 exhibit fatal lymphoproliferation and organ destruction by 2-3 weeks of age.
- Early treatment with murine CTLA4Ig (mCTLA4Ig) can delay the onset of this lymphoproliferative disease.
Purpose of the Study:
- To characterize T cells in CTLA-4-deficient mice before and after mCTLA4Ig treatment.
- To elucidate the role of CTLA-4 in regulating T-cell activation and differentiation.
Main Methods:
- Analysis of T-cell activation markers (CD69, IL-2R), homing receptors (CD62L), and in vitro proliferation.
- Assessment of T-cell survival, Bcl-xL expression, and cytokine secretion (IL-4, IL-5) upon TCR activation.
- Evaluation of CD28 costimulation and cytokine profiles following mCTLA4Ig treatment.
Main Results:
- CTLA-4-deficient T cells show hyperactivation, spontaneous proliferation, resistance to apoptosis (elevated Bcl-xL), and a Th2 cytokine bias (IL-4, IL-5).
- mCTLA4Ig treatment reversed T-cell hyperactivation and restored CD28 costimulation.
- T cells from treated mice were not skewed toward a Th2 phenotype.
Conclusions:
- CTLA-4 is crucial for regulating CD28-dependent peripheral T-cell activation.
- Dysregulation of CTLA-4 leads to apoptosis-resistant, Th2-polarized CD4+ T cells, contributing to lethal autoimmunity.