Abstract
Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we use an autoimmune mouse model, where MBCs are abundant, to show that the highest levels of LFA-1 and VLA-4 amongst B cells are found on MBCs. In vivo blockade of VLA-4 alone or in combination with LFA-1, but not LFA-1 alone, causes a release of MBCs from the spleen into the blood stream. In humans, we find that in peripheral blood, spleens, and tonsils from healthy donors the highest expression levels of the integrins LFA-1 and VLA-4 are also found on MBCs. Consistent with this, we found MBCs to have a higher capacity to adhere to ICAM-1 and VCAM-1 than naïve B cells. In patients with the autoimmune disease rheumatoid arthritis, it is the MBCs that have the highest levels of LFA-1 and VLA-4; moreover, compared with healthy donors, naïve B and MBCs of patients receiving anti-TNF medication have enhanced levels of the active form of LFA-1. Commensurate levels of the active αL subunit can be induced on B cells from healthy donors by exposure to the integrin ligands. Thus, our findings establish the selective use of the integrins LFA-1 and VLA-4 in the localization and adhesion of MBCs in both mice and humans.
Highlights
Interactions between integrins and their ligands are essential for maintaining the location of leukocytes in general, and mediate the extravasation of cells into tissues as well as their retention in peripheral lymphoid organs [1]
To determine whether the adhesion of mouse Memory B Cell (MBC) in the spleen depends on integrins, we treated Surrogate light chain (SLC)−/− mice with antibodies against Lymphocyte function-associated antigen 1 (LFA-1) and Very late antigen-4 (VLA-4)
Our blocking experiments demonstrate that both LFA-1 and VLA4 have a role to play, but that their differential expression on MBCs relative to marginal zone (MZ) B cells provides for selective placement of the subsets in lymphoid tissues, VLA-4 exerting the stronger pull for MBCs, and LFA-1 being the dominant influence on MZ B cells
Summary
Interactions between integrins and their ligands are essential for maintaining the location of leukocytes in general, and mediate the extravasation of cells into tissues as well as their retention in peripheral lymphoid organs [1]. As well as harboring MZ B cells, the spleen is an important reservoir for MBCs [7,8,9]; to date the mechanism of their retention there has not been identified, LFA-1 and/or VLA-4 integrins are obvious candidates for that role. We investigate this possibility using SLC−/− (surrogate light chain-deficient) mice, which share features with autoimmune mouse models, including spontaneous formation of germinal centers (GCs) and MBCs [3, 10,11,12]. In humans we examine the expression pattern of the LFA-1 and VLA-4 integrins in B-cell subsets from secondary lymphoid organs as well as functional properties of these integrins in PB of healthy donors and patients with rheumatoid arthritis
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