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Does CD40 ligation induce B cell negative selection?
Jesús Martínez-Barnetche1, Vicente Madrid-Marina, Richard A Flavell
1Research Unit on Autoimmune Diseases, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 03020 México City, Distrito Federal, México.
Journal of Immunology (Baltimore, Md. : 1950)
|January 22, 2002
Summary
Early CD40 signaling in B cells during development leads to nonfunctional B cells. This CD40 ligation triggers negative selection, halting B cell maturation and function.
Area of Science:
- Immunology
- Developmental Biology
- Cell Biology
Background:
- CD40 signaling is crucial for mature B cell activation and differentiation.
- The role of CD40 in early B cell development (ontogeny) remains unclear.
- CD40 is expressed on B cell precursors, but its function at this stage is unknown.
Purpose of the Study:
- To investigate the effects of CD40 ligation during B cell ontogeny.
- To analyze the impact of constitutive CD154 expression on B cell development in transgenic mice.
- To determine the functional consequences of early CD40 signaling on B cell populations.
Main Methods:
- Generation of transgenic mice (kappaEP-CD154) with constitutive CD154 expression on B cells.
- Analysis of B cell precursor populations in fetal liver and adult bone marrow.
- Flow cytometry to assess surface marker expression (CD154, CD23, MHC class II, CD5, Fas) on B cells.
- Quantification of peripheral B cell numbers and assessment of serum immunoglobulin levels (hypogammaglobulinemia).
Main Results:
- Absence of B cell precursors beyond pro-B cells in adult bone marrow of kappaEP-CD154 mice.
- Increased B cell precursors in fetal liver and a significant expansion of peripheral B cells in newborns.
- Newly generated B cells exhibited markers of activation (CD23, MHC class II) but were nonfunctional, leading to hypogammaglobulinemia.
- B cells underwent CD5/Fas expression and subsequent reduction in the periphery in a CD154-CD40-dependent manner.
Conclusions:
- CD40 ligation during B cell ontogeny induces negative selection.
- This process results in either hyporesponsiveness or an arrest in B cell maturation.
- The timing and location of CD40 signaling influence the outcome of B cell development.