Abstract
Complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) of myeloid cells are known for long to participate in actin linked functions like phagocytosis, adhesion, and migration. The expression and role of these two β2-integrins however, in human B lymphocytes have only scarcely been studied so far, although it has been shown recently that CD11c+ B cells are mainly memory cells. In our systematic study we investigated B cells isolated from tonsils and peripheral blood of healthy donors. We found, that while only 5% of resting tonsillar B cells expressed CD11c, their number increased up to 26% after 3 days of BCR stimulation. Lower, but still remarkable percentage of B lymphocytes were positive for CD11c after stimulation via TLR9 alone or via TLR9 and BCR simultaneously. At the same time, we detected no significant expression of CD11b on resting or activated tonsillar B cells. Blood B lymphocytes showed a similar expression pattern of both β2-integrins. We demonstrated that CD11c molecules appearing on the surface of B cells are newly synthesized, reaching the number of 9,500 per activated B cell. We found that CR4 expressing B cells belong to the memory pool and the increase of CD11c expression on tonsillar B cells upon BCR mediated activation occurs parallel with class switching. Analysis of the function of CD11c revealed, that this β2-integrin contributes to the adhesion and migration of activated B lymphocytes. We also demonstrated that the CR4 mediated adhesion promotes the proliferation of the BCR activated cells. Our studies are the first to demonstrate that CD11c expressed on BCR-activated human B cells are not only passive markers but functional drivers of memory B cell responses.
Highlights
Integrins mediate versatile functions that are associated with cell-cell and cellextracellular matrix interactions, controlling the response to different environmental stimuli
We prove that CR4 on B-cell receptor (BCR) activated tonsillar B lymphocytes is not merely a passive marker, but it contributes to the adhesion and migration of the cells, CR4 mediated adhesion enhances the proliferation of memory B lymphocytes
In the case of blood-derived B cells we found that BCR stimulation was the strongest trigger to induce CD11c expression, while lower percentages of B lymphocytes were positive for CD11c after stimulation via TLR9 alone or via TLR9 and BCR combined
Summary
Integrins mediate versatile functions that are associated with cell-cell and cellextracellular matrix interactions, controlling the response to different environmental stimuli. Integrins expressed on the cell membrane are mostly in their inactive state, which allows free circulation of leukocytes in blood vessels Their activation is conformationally regulated and can be induced by intracellular and extracellular stimuli leading to a “switchblade-like” conformational change. Complement receptors CR3 (CD11b/CD18, known as Mac-1, αMβ2) and CR4 (CD11c/CD18, designated as p150,95; αXβ2) are members of the β2 integrin family While they contain the same β chain and the extracellular region of their α chain is very similar (showing 87% homology), the cytoplasmic tail of CD11b and CD11c has a highly different structure. This variance leads to functional differences between CR3 and CR4, as the kinetics of activation of β2 integrins and their ability to associate with signaling or actin-binding proteins depend on their cytoplasmic domain, including the intracellular tail of the α chain [2,3,4]
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