Differential Intrasplenic Migration of Dendritic Cell Subsets Tailors Adaptive Immunity

Abstract

Evidence suggests that distinct splenic dendritic cell (DC) subsets activate either CD4+ or CD8+ T cells in vivo. This bias has been partially ascribed to differential antigen presentation; however, all DC subsets can activate both T cell lineages in vitro. Therefore, we tested whether the organization of DC and T cell subsets in the spleen dictated this preference. We discovered that CD4+ and CD8+ T cells segregated within splenic T cell zones prior to immunization. After intravenous immunization, the two major conventional DC populations, distinguished by 33D1 and XCR1 staining, migrated into separate regions of the T cell zone: 33D1+ DCs migrated into the CD4+ T cell area, whereas XCR1+ DCs migrated into the CD8+ T cell area. Thus, the post-immunization location of each DC subset correlated with the T cell lineage it preferentially primes. Preventing this co-localization selectively impaired either CD4+ or CD8+ T cell immunity to blood-borne antigens.

Distinct oxysterol requirements for positioning naïve and activated dendritic cells in the spleen

“…XCR1 is expressed by ~85% of splenic CD8α + DCs, and these cells are localized in the T cell zone, MZ, and RP in naïve mice (5–9). These DCs up-regulated CCR7 and CD86 but not EBI2 within 6 hours of SRBC immunization (Fig.…”

“…These DCs move into the T cell zone after activation (8, 9, 42). Our finding that CD8α + DCs up-regulate CCR7 but not EBI2 under the activation conditions tested provides a possible explanation for why they were not enriched in the outer T cell zone.…”

“…XCR1 + cDC1s are present in the MZ, RP, and T cell zone (5–9). After exposure to activating stimuli such as sheep red blood cells (SRBCs), lipopolysaccharide (LPS), or the double-stranded RNA mimetic polyinosinic:polycytidylic acid (poly I:C), splenic DCs move rapidly into the splenic T cell zone and, in some cases, position preferentially along the B-T zone interface (3, 10–16).…”

“…Positioning at the B-T zone interface likely increases the amount of encounter with activated CD4 + T cells because they also favor this location (17, 18). DC movement into the T cell zone involves CCR7 up-regulation (3, 9, 11, 19). However, the factors that allow activated DCs to distinguish between the outer and the inner T cell zone are not defined.…”

DOCK8 regulates signal transduction events to control immunity

“…Similarly, DOCK8 regulates Cdc42 activation in dendritic cells, which is required for their accumulation in the lymph node for T-cell priming. [26][27][28] More recently, DOCK8 was also shown to regulate macrophage migration through an interaction with LRAP35, linking Cdc42 to actomyosin dynamics. 29 Thus, in this context, DOCK8 can activate Cdc42, but also function as an adaptor/ scaffold molecule to link Cdc42 to the cytoskeleton.…”