Stromal cell modulation of negative regulatory signals that influence apoptosis and proliferation of B lineage lymphocytes.
The bone marrow microenvironment influences whether a given B cell proliferates, differentiates, or undergoes apoptosis. In this report, we demonstrate that apoptosis of primary murine B lymphocyte precursors can be regulated either positively or negatively by stroma. Several stromal lines that support lymphocyte outgrowth suppressed the spontaneous apoptosis of pre-B cells by as much as 90%. Direct contact with stromal cells more effectively protected lymphocytes than did stromal cell-CM or a collection of recombinant cytokines. In contrast, one unique stromal cell clone actually induced lymphocyte apoptosis, and a second line appeared inert. A survey of adherent cell lines suggested that expression of life-sparing molecules is widespread but not ubiquitous. Experiments with neutralizing Abs to CD44, vascular cell adhesion molecule-1 (VCAM-1), CD9, intercellular adhesion molecule-1 (ICAM-1), or ICAM-2 suggested that these interaction molecules do not deliver short-term survival signals to B cell precursors. Of particular interest, direct interaction with lymphocyte-supportive stromal cells minimized the negative regulatory effects of IL-1alpha, and a glucocorticoid, but not IFN-beta or PGE2. These results demonstrate that the effect of negative regulators depends upon the context in which these signals are presented. As molecules that influence B lymphopoiesis are better defined, it will be important to consider the role of each in combination with other stimuli.
Borghesi
L A
LA
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
Smithson
G
G
Kincade
P W
PW
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D019070:Cell Lineage; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology*
D015815:Cell Adhesion Molecules