Critical Requirement of CD11b (Mac-1) on T Cells and Accessory Cells for Development of Experimental Autoimmune Encephalomyelitis

Abstract

Mac-1 (CD18/CD11b) is a member of the β2-integrin family of adhesion molecules and is implicated in the development of many inflammatory diseases. The role of Mac-1 in the development of CNS demyelinating diseases, including multiple sclerosis, is not understood, and Ab inhibition studies in experimental allergic encephalomyelitis (EAE), the animal model for multiple sclerosis, have produced conflicting findings. To clarify these results and to determine Mac-1-mediated mechanisms in EAE, we performed EAE using Mac-1-deficient mice. Mac-1 homozygous-deficient, but not Mac-1 heterozygous-deficient mice, had significantly delayed onset and attenuated EAE. Leukocyte infiltration was similar in both groups of mice in early disease but significantly reduced in spinal cords of receptor-deficient mice in late disease. Adoptive transfer of Ag-restimulated T cells from wild-type to Mac-1-deficient mice produced significantly attenuated EAE, whereas transfer of Mac-1-deficient Ag-restimulated T cells to control mice failed to induce EAE. T cells from myelin oligodendrocyte glycoprotein (MOG)35–55 peptide-primed Mac-1-deficient mice displayed an altered cytokine phenotype with elevated levels of TGF-β and IL-10, but reduced levels of IL-2, IFN-γ, TNF-α, IL-12, and IL-4 compared with control mice. Mac-1-deficient T cells from primed mice proliferated comparably to that of control T cells on MOG35–55 restimulation in vitro. However, the draining lymph nodes of MAC-1-deficient mice on day 10 after MOG35–55 immunization contained lower frequency of blast T cells than in control mice, suggesting poor priming. Our results indicate that Mac-1 expression is critical on both phagocytic cells and T cells for the development of demyelinating disease.

Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease

“…In contrast, Calida and colleagues reported that deletion of C3 had essentially no effect on the course of EAE compared to control mice (Calida et al, 2001). Since the publication of both sets of data, a number of other studies from our group have demonstrated that receptors for C3-derived activation fragments, including the C3aR and CR3 (Mac-1; CD18/CD11b), are critical for the development of EAE (Boos et al, 2004;Bullard et al, 2005). These more recent findings prompted us to re-examine the role of C3 in EAE.…”

“…iC3b promotes CR3-mediated phagocytosis, thus blockade of iC3b-CR3 interaction by treatment with anti-CR3 antibodies inhibits demyelination in vitro and in vivo (reviewed in Barnum and Szalai, 2006). Furthermore, deletion of CR3 significantly attenuates EAE, in part through CR3-dependent effector functions on T cells (Bullard et al, 2005). This raises the possibility that iC3b directly modulates T cell function(s) and that the absence of iC3b costimulation during EAE diminishes the potency of encephalitogenic T cells.…”

“…Thus deletion of C3, the C3a receptor, or the iC3b receptor (a.k.a. CR3 or Mac-1) attenuates the severity of EAE and reduces leukocyte infiltration into the CNS, while transgenic expression of C3a in the CNS markedly exacerbates EAE (Boos et al, 2004;Bullard et al, 2005;Nataf et al, 2000). In contrast deletion of C5, C5-derived fragments, and their associated receptors has no effect on the course of EAE (Reiman et al, 2002;Reiman et al, 2005;Weerth et al, 2003).…”

Production of CCL2 by Central Nervous System Cells Regulates Development of Murine Experimental Autoimmune Encephalomyelitis through the Recruitment of TNF- and iNOS-Expressing Macrophages and Myeloid Dendritic Cells

“…Disease pathogenesis is thought to result from the activation of autoreactive CD4 (3,4) or CD8 (5) IL-17-producing (6) T cells in the periphery, the migration of these activated T cells (7) through CD49d- (8,9) and ␤-integrin-mediated (10,11) mechanisms into the CNS, and their reactivation by CNS myeloid dendritic cells (DC) (12). In addition to the requirement for autoreactive T cells, macrophages have been shown to be necessary for EAE development (13)(14)(15).…”

p150/95 (CD11c/CD18) Expression Is Required for the Development of Experimental Autoimmune Encephalomyelitis

“…14,[27][28][29][30][31] Studies have also suggested a role for p150/95 in monocyte/endothelium interactions or conjugate formation between cytotoxic T cells and target cells of various types, 14,18,[32][33][34][35] but the in vivo relevance of these findings remains unclear. These studies combined with our previous work demonstrating an important role for the other iC3b receptor, Mac-1, in the development and progression of EAE 6 prompted us to examine the role of p150/95 in this animal model of autoimmune demyelinating disease.…”