Modulation of tolerogenic dendritic cells and autoimmunity

Abstract

A key function of dendritic cells (DCs) is to induce either immune tolerance or immune activation. Many new DC subsets are being recognized, and it is now clear that each DC subset has a specialized function. For example, different DC subsets may express different cell surface molecules and respond differently to activation by secretion of a unique cytokine profile. Apart from intrinsic differences among DC subsets, various immune modulators in the microenvironment may influence DC function; inappropriate DC function is closely related to the development of immune disorders. The most exciting recent advance in DC biology is appreciation of human DC subsets. In this review, we discuss functionally different mouse and human DC subsets both in lymphoid organs and non-lymphoid organs, the molecules that regulate DC function, and the emerging understanding of the contribution of DCs to autoimmune diseases.

Keywords: Autoimmunity; Dendritic cells; Tissue-resident dendritic cells; Tolerogenic dendritic cells.

Fig. 1.

DC commitment and differentiation. The illustration shows that DCs and monocytes originated from a common myeloid progenitor (CMP) which is derived from hematopoietic stem cells (HSC). HSCs give rise to common lymphoid progenitors (CLPs) and CMPs. CMPs differentiate into granulocyte macrophage progenitors (GMPs), which differentiate into granulocyte and macrophage DC progenitors (MDP). MDPs give rise to monocytes and common DC progenitors (CDP), and CDPs further differentiate into plasmacytoid DCs (pDC) or pre-DCs. Pre-DCs can migrate out of bone marrow and undergo final differentiation into CD8α+ DCs or CD11b+ DCs in lymphoid organs or CD103+ DCs or CD11b+ DCs in non-lymphoid tissue. Shaded box represents bone marrow.

Fig. 2.

Regulation of DC function by soluble factors. Various soluble proteins regulate function of DCs. Csf-2 which is expressed during inflammation, binds to Csf-2 receptor in DCs leading to increase CD103+ cDC survival. Csf-2R engagement also increases CD103 expression in cDCs in a stat5-dependent fashion. A low level of circulating IL-6 can trigger gp130 activation and inhibit stat3 activation in DCs. This signaling is required to maintain an immature DC phenotype. HMGB1 secreted from necrotic cells can bind to RAGE or TLR4 on the surface of DCs, and activate NFκB signaling pathway leading to upregualtion of co-stimulatory molecule expression and secretion of proinflammatory cytokines. Regulation by C1q on DCs occurs through multiple receptors. C1q can bind to C1q receptors (gC1qR, C1qRp and collectin), DC-SIGN, collagen receptor, LAIR-1 and dispose of apoptotic debris. C1q binding to C1q receptors might execute signaling alone or by cross-talk between receptors. The consequence of C1q binding to receptors is downregulation of proinflammatory cytokine expression and blocking of monocytes to DC differentiation.