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Emerging evidence suggests that the β 2 integrin family of adhesion molecules have an important role in suppressing immune activation and inflammation. β 2 integrins are important adhesion and signaling molecules that are exclusively expressed on leukocytes. The four β 2 integrins (CD11a, CD11b, CD11c, and CD11d paired with the β 2 chain CD18) play important roles in regulating three key aspects of immune cell function: recruitment to sites of inflammation; cell-cell contact formation; and downstream effects on cellular signaling. Through these three processes, β 2 integrins both contribute to and regulate immune responses. This review explores the pro- and anti-inflammatory effects of β 2 integrins in monocytes, macrophages, and dendritic cells and how they influence the outcome of immune responses. We furthermore discuss how imbalances in β 2 integrin function can have far-reaching effects on mounting appropriate immune responses, potentially influencing the development and progression of autoimmune and inflammatory diseases. Therapeutic targeting of β 2 integrins, therefore, holds enormous potential in exploring treatment options for a variety of inflammatory conditions.

Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19. These MPLA-tDCs induced hyporesponsiveness of autologous CD4+ T cells specific for synovial antigens in vitro . Global transcriptome analysis confirmed a unique transcriptional profile of MPLA-tDCs and revealed that RA-associated genes, which were upregulated in untreated DCs from RA patients, returned to expression levels of healthy donor-derived DCs after treatment with dexamethasone and MPLA. Thus, monocyte-derived DCs from RA patients have the capacity to develop tolerogenic features at transcriptional as well as at translational level, when modulated with dexamethasone and MPLA, overcoming disease-related effects. Furthermore, the ability of MPLA-tDCs to impair T cell responses to synovial antigens validates their potential as cellular treatment for RA.

Tolerogenic dendritic cells (DCs) are a promising tool to control T cell-mediated autoimmunity. Here, we evaluate the ability of dexamethasone-modulated and monophosphoryl lipid A (MPLA)-activated DCs [MPLA-tolerogenic DCs (tDCs)] to exert immunomodulatory effects on naive and memory CD4 + T cells in an antigen-specific manner. For this purpose, MPLA-tDCs were loaded with purified protein derivative (PPD) as antigen and co-cultured with autologous naive or memory CD4 + T cells. Lymphocytes were re-challenged with autologous PPD-pulsed mature DCs (mDCs), evaluating proliferation and cytokine production by flow cytometry. On primed-naive CD4 + T cells, the expression of regulatory T cell markers was evaluated and their suppressive ability was assessed in autologous co-cultures with CD4 + effector T cells and PPD-pulsed mDCs. We detected that memory CD4 + T cells primed by MPLA-tDCs presented reduced proliferation and proinflammatory cytokine expression in response to PPD and were refractory to subsequent stimulation. Naive CD4 + T cells were instructed by MPLA-tDCs to be hyporesponsive to antigen-specific restimulation and to suppress the induction of T helper cell type 1 and 17 responses. In conclusion, MPLA-tDCs are able to modulate antigen-specific responses of both naive and memory CD4 + T cells and might be a promising strategy to "turn off" self-reactive CD4 + effector T cells in autoimmunity.