Greatly reduced lymphoproliferation in lpr mice lacking major histocompatibility complex class I

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Mice with the lpr gene have a defective fas (CD95) receptor, leading to lymphoproliferation.
• This defect causes accumulation of CD4-CD8- (double negative [DN]) T cells, autoantibody production, and organ damage.
• Previous research suggested a role for major histocompatibility complex (MHC) class I in DN T cell development.

Purpose of the Study:

• To investigate the role of MHC class I in the development of DN T cells in lpr mice.
• To determine the lineage and selection mechanisms of the aberrant DN T cell population.

Main Methods:

• Generated C57BL/6-lpr/lpr mice lacking beta 2-microglobulin (beta 2m) for complete MHC class I deficiency.
• Compared lymphadenopathy, T cell subset populations (including DN, gamma/delta T cells), and autoantibody production between MHC class I-deficient and control lpr mice.
• Analyzed T cell receptor V beta expression in DN T cells to determine repertoire and selection.

Main Results:

• Mice lacking MHC class I (beta 2m lpr) showed significantly reduced lymphadenopathy and DN T cell numbers.
• A shift in T cell receptor V beta expression indicated a reduction in CD8 lineage-derived DN T cells and unmasking of a minor CD4-like population.
• Autoantibody production (IgG antichromatin, anti-ssDNA) was significantly reduced in MHC class I-deficient lpr mice.

Conclusions:

• Over 90% of DN T cells in lpr mice are derived from the CD8 lineage and selected by MHC class I.
• A minor T cell subset selected by MHC class II and gamma/delta T cells are also affected by the lpr defect.
• MHC class I plays a critical role in the aberrant expansion of DN T cells in lpr mice.