Beyond CCR7: dendritic cell migration in type 2 inflammation

Abstract

Conventional dendritic cells (cDCs) are crucial antigen-presenting cells that initiate and regulate T cell responses, thereby shaping immunity against pathogens, innocuous antigens, tumors, and self-antigens. The migration of cDCs from peripheral tissues to draining lymph nodes (dLNs) is essential for their function in immune surveillance. This migration allows cDCs to convey the conditions of peripheral tissues to antigen-specific T cells in the dLNs, facilitating effective immune responses. Migration is primarily mediated by chemokine receptor CCR7, which is upregulated in response to homeostatic and inflammatory cues, guiding cDCs to dLNs. However, during type 2 immune responses, such as those triggered by parasites or allergens, a paradox arises-cDCs exhibit robust migration to dLNs despite low CCR7 expression. This review discusses how type 2 inflammation relies on additional signaling pathways, including those induced by membrane-derived bioactive lipid mediators like eicosanoids, sphingolipids, and oxysterols, which cooperate with CCR7 to enhance cDC migration and T helper 2 (Th2) differentiation. We explore the potential regulatory mechanisms of cDC migration in type 2 immunity, offering insights into the differential control of cDC trafficking in diverse immune contexts and its impact on immune responses.

Keywords: 7α,25-Dihydroxycholesterol (7α,25-OHC); CCR7; EBI2 (GPR183); cysteinyl leukotrienes (cysLTs); dendritic cell migration; prostaglandins (PGs); sphingosine-1-phosphate (S1P); type 2 immune responses.

Figure 1

CCR7-dependent steps in cDC migration and localization in the dLN. CCR7 and its ligands, CCL21 and CCL19, orchestrate the migration and positioning of cDCs during both steady-state and immune responses. cDC migration from peripheral tissues to the dLN occurs in three distinct steps, each with specific roles for CCL21 and CCL19: 1) Entry into afferent lymphatics: tissue-resident cDCs enter lymphatic capillaries guided by CCL21, which is constitutively expressed by lymphatic endothelial cells. 2) Transition through the SCS: after traveling passively through afferent lymphatic vessels, cDCs reach the SCS of the dLN, where ACKR4 shapes CCL21 gradients, enabling cDCs to cross into the dLN parenchyma. 3) Positioning in the T Cell Areas: within the dLN, cDCs follow CCL21 and CCL19 gradients to localize in T cell areas, inducing tolerance to self-antigens or facilitating pathogen-specific responses, such as Th1 and Th17 immunity. In type 2 immunity, characterized by low CCR7 expression on cDCs, their migration to the dLN remains efficient, but their localization is restricted to perifollicular areas, where they support Th2 responses. These CCR7-regulated positioning differences underscore the role of cDCs in tailoring immune responses based on the pathogen type, inflammatory context, or steady-state conditions. The mechanisms enabling cDC trafficking during type 2 inflammation, despite low CCR7 activity, remain an open question. Figure created with Biorender.

Figure 2

Biosynthesis pathways and receptors of AA-derived eicosanoids and their influence on cDC migration. Eicosanoids are bioactive lipids primarily derived from AA, a 20-carbon polyunsaturated fatty acid released from membrane phospholipids by cPLA2. AA metabolism occurs through two main biosynthetic pathways: the COX pathway and the LOX pathway. In the COX pathway, constitutive COX-1 and inducible COX-2 enzymes convert AA into PGH2, a precursor for various prostanoids, including prostaglandins, prostacyclin, and thromboxanes. PGE2, synthesized via COX-2 and PGES, acts on EP1-4 receptors. PGE2 signaling through EP2 and EP4 receptors on cDCs enhances CCR7 expression and function, promoting cDC migration toward dLNs and facilitating their localization within the T cell areas. PGD2, produced through the COX-2/PGDS pathway, signals via DP1 and DP2 (CRTH2) receptors. Unlike PGE2, PGD2 signaling through DP1 receptors on DCs downregulates CCR7 expression and enhances their ability to promote Th2 cell differentiation. In the LOX pathway, 5-LOX converts AA into 5-HPETE and LTA4. LTA4 is further processed into leukotrienes. LTC4 synthase/LTC4S catalyzes the formation of LTC4, which is subsequently converted to LTD4 and LTE4. LTC4, LTD4, and LTE4, collectively known as cysteinyl leukotrienes, interact with CysLT1, CysLT2, and CysLT3 receptors. On DCs, CysLT1 receptor signaling supports CCR7-mediated mobilization of cDCs from peripheral tissues to dLNs. Additionally, LTA4 hydrolase/LTA4H produces LTB4, which binds to BLT1 and BLT2 receptors and acts as a potent chemoattractant for neutrophils. Overall, during steady-state and type 1/type 17 immune responses, the PGE2 signaling pathway enhances CCR7 expression and CCR7-dependent cDC migration. However, during the initiation of type 2 immunity, the LOX and COX pathways are activated and interact, particularly through mediators such as LTC4, LTD4, and PGD2. This coordinated mechanism promotes Th2 cell-mediated immunity while ensuring efficient guidance of DCs to dLNs under conditions of reduced CCR7 activity. Figure created with Biorender.

Figure 3

Pathway of S1P synthesis and influence on cDC migration. S1P is synthesized through the hydrolysis of sphingomyelin, a major sphingolipid in the plasma membrane, into ceramide. Ceramide is then metabolized by ceramidase into sphingosine, which is subsequently phosphorylated by SphK1/2 to produce S1P. S1P can be exported from cells via membrane transporters and acts through G-protein-coupled receptors, S1PR1-5. When S1P binds to S1PR1 on immune cells (such as T cells, B cells, and cDCs) residing in LNs, it promotes their exit from the LNs by overriding retention signals mediated by CCR7. This process involves S1P-driven migration of these cells through efferent lymphatics into the thoracic duct, ultimately reaching the bloodstream. Notably, cDC2s, but not cDC1s, migrate out of the LNs. This difference is likely due to variations in CCR7 expression, with cDC1s exhibiting higher CCR7 levels, leading to their retention in the LNs. In situations where CCR7 is not strongly upregulated on tissue cDCs, S1P/S1PR interactions may also facilitate the migration of cDCs from peripheral tissues to dLNs. Figure created with Biorender.

Figure 4

Biosynthesis and role of 7α,25-OHC in cDC localization within secondary lymphoid organs. 7α,25-OHC, an oxysterol derived from cholesterol, is crucial for the precise positioning of immune cells within secondary lymphoid tissues, such as LNs and the spleen, by acting as a ligand for the G-protein-coupled receptor EBI2 (GPR183). 7α,25-OHC biosynthesis involves two steps: cholesterol is first converted to 25-OHC by CH25H, and then 25-OHC is hydroxylated at the 7α-position by the cytochrome P450 enzyme CYP7B1 to form 7α,25-OHC. In LNs and the spleen, 7α,25-OHC is primarily produced at the borders of B cell follicles. By binding to EBI2, 7α,25-OHC directs the migration of immune cells, including B cells, T cells, and cDC2s, to perifollicular regions surrounding B cell follicles. This positioning is regulated by counteracting the chemotactic signals of two other receptor-ligand systems: CCR7-CCL19/CCL21 and CXCR5-CXCL13. CCL19 and CCL21, the ligands for CCR7, are produced in T cell areas and guides CCR7-expressing cells to these zones, while CXCL13, the ligand for CXCR5, is produced within B cell follicles and attracts CXCR5-expressing cells into the follicles. Thus, the localization of cells to T cell areas, B cell follicles, or perifollicular regions, including the T-B boundary and interfollicular locations, depends on the coordinated actions of EBI2-, CCR7-, and CXCR5-dependent signaling pathways. Migratory cDCs, particularly cDC2s, can express all three receptors—CCR7, CXCR5, and EBI2—but their expression levels vary depending on their activation state. During type 2 inflammation, low CCR7 expression combined with upregulation of CXCR5 and EBI2 facilitates the guidance of cDC2s and CD4⁺ T cells to the T-B cell boundary and peri- and inter-follicular regions in response to the ligands for these receptors. Such localization is essential for initiating Th2 and Tfh cell responses. Thus, the coordinated actions of EBI2-, CCR7-, and CXCR5-dependent signaling pathways are crucial for the effective localization and function of cDCs and cognate T cells during the initiation of type 2 immunity. Figure created with Biorender.