Active MAC-1 (CD11b/CD18) on DCs inhibits full T-cell activation

Abstract

The ␤ 2 integrins are important for transendothelial migration of leukocytes as well as for T-cell activation during antigen presentation. Despite abundant expression of ␤ 2 integrins on antigen-presenting cells (APCs), their functional relevance for antigen presentation is completely unclear. We show here that dendritic cells (DCs) from CD18-deficient mice, which lack all functional ␤ 2 integrins, have no defect in antigen presentation. Moreover, DCs from normal mice express inactive ␤ 2 integrins that do not become activated on contact with T cells, at least in vitro. Pharmacologic activation of ␤ 2 integrins on DCs results in a significant reduction of their T cell-activating capacity. This effect is mediated by Mac-1 (CD11b/CD18) on DCs because it could be reversed via blocking antibodies against CD18 and CD11b. Furthermore, the antigen-presenting capacity of macrophages, which express constitutively active ␤ 2 integrins, is significantly enhanced on Mac-1 blockade. We therefore conclude that active CD11b/ CD18 ( IntroductionThe ␤ 2 integrins (CD11/CD18) are heterodimeric leukocyte adhesion molecules exclusively expressed on hematopoietic cells. They play an important role for cell-to-cell contacts between leukocytes as well as for contacts between leukocytes and endothelial cells. 1,2 The common ␤ chain (CD18) associates with 4 different ␣ subunits, ␣L, ␣M, ␣X, and ␣D, forming distinct functional heterodimers termed leukocyte functional antigen-1 (LFA-1, CD11a/CD18), Mac-1 (CD11b/CD18), gp150,95 (CD11c/CD18), and CD11d/CD18. [2][3][4] These interact with more than 20 ligands, many of which belong to the family of ICAMs. 5,6 Adhesion between T cells and antigen-presenting cells (APCs) is necessary for the formation of the immunologic synapse (IS). 7,8 Interactions between LFA-1 on the surface of T cells and intercellular adhesion molecules ICAM-1, 2, and 3 (in humans) on the APC surface were described to be involved in formation of the IS. 9,10 Moreover, ligation of LFA-1 on T cells is required for optimal activation and differentiation of T cells, [11][12][13][14][15][16][17][18][19][20][21] although the downstream signaling events are still not fully understood. On T cells, experiments with blocking antibodies against LFA-1 and with LFA-1-deficient T cells have shown that those T cells are impaired in numerous effector functions. [22][23][24] Dendritic cells (DCs), on the other hand, are known to be the most relevant APCs in the immune system. 25,26 DCs express at least 3 ␤ 2 integrins, LFA-1 (CD11a/CD18), Mac-1 (CD11b/ CD18), and gp150,95 (CD11c/CD18). 27,28 Compared to LFA-1 on T cells, very little information is available about the role and function of ␤ 2 integrins on DCs, especially regarding the process of antigen presentation and T-cell activation. Studies with splenocytes of mice deficient in CD11a, CD11b, CD11c, and CD11d showed impaired T-cell activation in CD11a-, CD11b-, and CD11d-deficient splenocytes on stimulation with superantigen, but this was due to dysfunctional T cells rather than a de...

Cysteine protease cathepsin X modulates immune response via activation of β2 integrins

“…Similarly, in a MLR, alloantigen-induced T-cell proliferation could be increased by Mac-1 inhibition. 15 In the present study, the inhibition of cathepsin X by 2F12 mAb also markedly enhanced proliferation of PBMC. The proliferation was increased by CA-074, an inhibitor of cathepsins B and X, showing that the effect is attributable to the inhibition of cathepsin X activity and not to non-specific action of the monoclonal antibody.…”

“…15,34,35 As mentioned previously, Mac-1 activity interferes with LFA-1 mediated aggregation 30 and it has been proposed that dysregulated adhesion and formation of immunological synapse caused by Mac-1 activity might explain down-regulated T-cell activation. 15 In this regard, it has been proposed that via constitutively active Mac-1 on macrophages, in contrast to functionally inactive Mac-1 on dendritic cells, antigen presentation in vivo is restricted to dendritic cells. 15 As shown in our previous study, the localization of cathepsin X in macrophages differs from that in dendritic cells, 17 which may have an impact on different regulation of Mac-1 receptors in the two cell types.…”

“…p150,95 is expressed by human monocytes, granulocytes, natural killer (NK) cells, and some lymphocytes, and can function as an adhesion molecule and interact with a counter-receptor on stimulated endothelium. 12 It has been shown that the functional activity of LFA-1 is involved in the activation of T-cell proliferation and consequently the immune response, whereas the activity of Mac-1 suppresses it [13][14][15] (see Fig. 1).…”

“…27,28 In recent studies, it has been shown that the constitutive activity of Mac-1 on antigen-presenting cells inhibits antigen presentation and down-regulates T-cell activation, 15,29 presumably because of suppression of inflammatory cytokine release. 29 The antibodies directed against CD11/CD18 inactivate Mac-1 activity, 28 vice versa, the inhibition of cathepsin X by 2F12 mAb diminishes adhesion of monocytes through the Mac-1 receptor 16 and enhances T lymphocyte proliferation.…”

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

“…Our previous reports showed that CD11b is able to maintain immunological tolerance and inhibit inflammatory responses by repressing TLR3 signaling in NK cells and TLR4 signaling in macrophages (15,16). Analogously, CD11b, abundantly expressed in DCs, can inhibit DC-primed CD4 + T cell activation and promote peripheral tolerance by breaking Th17 differentiation (17,18). These reports suggested roles for CD11b in the regulation of T cell adaptive immunity.…”