Activated Human Memory B Lymphocytes Use CR4 (CD11c/CD18) for Adhesion, Migration, and Proliferation

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 β 2 -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 β 2 -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 β 2 -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.

BCR activated CLL B cells use both CR3 (CD11b/CD18) and CR4 (CD11c/CD18) for adhesion while CR4 has a dominant role in migration towards SDF-1

“…In the case of healthy donors it has been found, that these receptors are scarcely expressed on nonactivated B lymphocytes [4,5], but after activation by different stimuli they appear on certain B cell populations [5][6][7][8][9][10]. We found lately that activated human memory B lymphocytes use CR4 for adhesion, migration, and proliferation [11].…”

“…Recently, our group demonstrated that both CR3 and CR4 are involved in the spreading of CpG-activated CLL B cells on fibrinogen [4]. Moreover, since activated B cells of healthy donors use CR4 for adhesion, migration, and proliferation [11], we suggest that CR4 may have a similar role in CLL B cells too, as malignant cells represent the activated state of their normal counterpart.…”

“…Since CD11b and CD11c are known to be expressed by various malignant B cells [4,[12][13][14][15][16][17][18][19], first we tested whether the cells of the EBV-negative Burkitt-like lymphoma line BJAB could serve as a model for examining the role of CR3 or CR4 expressed by malignant human B cells. Flow cytometry measurements revealed that BJAB cells are positive for CD11c, but negative for CD11b (Fig 1A), similarly to the activated B cells of healthy donors [11]. As CR4 was found to be involved in the adhesion of activated normal B cells [11], we set out to measure the adhesive capacity of BJAB cells to fibrinogen, the natural ligand of CR4.…”

Biologia Futura: stories about the functions of β2-integrins in human phagocytes

“…In humans, CD11b and CD11c are simultaneously present on a wide variety of leukocytes, but they are expressed on phagocytes in the greatest number (Erdei et al 2017;Nagy-Baló et al 2020). Moreover, CD11c is a generally accepted myeloid marker in humans.…”

“…The complement receptors CR3 and CR4 are expressed on monocytes, macrophages, dendritic cells, neutrophils and natural killer cells, and recently they have been detected on certain B lymphocyte populations in human (Erdei et al 2017;Nagy-Baló et al 2020).…”