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Recruitment of dendritic cells (DCs) to lymph nodes (LNs) is pivotal to the establishment of immune response. Whereas DCs have been proven to undergo afferent lymphatic pathway to enter LNs from peripheral tissues, a question remains if DCs also migrate into LNs directly from the circulation. Here we demonstrate that plasmacytoid DC (pDC) precursors can transmigrate across high endothelial venules (HEVs) of inflamed LNs in mice. Bacterial infection induces a significant number of pDC and myeloid DC (mDC) precursors into the circulation. Both subsets express a common set of chemokine receptors except CXCR3, display parallel mobilization into the blood, but show distinct trafficking pathway to the LNs. In a short-term homing assay, whereas mDC precursors migrate to peripheral tissues and subsequently to draining LNs, pDC precursors directly enter the LNs in a CXCL9 and E-selectin dependent manner. Tumor necrosis factor-alpha controls not only DC precursor mobilization into the blood but also chemokine up-regulation on LN HEVs. A similar trafficking pathway is observed also in viral infection, and CXCR3(-/-) mice-derived pDC precursors show defective trans-HEV migration. This study clarifies the inflammation-dependent, chemokine-driven distinct property of DC precursor trafficking.

Cryptopatches (CP) are murine gut anatomical sites for generating thymus-independent intraepithelial T lymphocytes (IEL). However, it remains elusive how lympho-hematopoietic progenitor cells migrate from bone marrow (BM) into CP and differentiate into IEL. Here we show that mice reconstituted with BM-derived c-kit(+) cells express CCL25 (TECK)-intrakine gene, which reduces specifically the chemotactic response to CCL25 but not CXCL12 in the thymocytes. These mice exhibited a dramatic reduction of CP and IEL in the small intestine, and harbored conspicuously decreased numbers of c-kit(+) cells in the emaciated CP. In contrast, T cells in the thymic, splenic and lymph node compartments developed normally in these mice. Importantly, it was demonstrated that CD11c(+) dendritic stromal cells in CP expressed CCL25 and c-kit(+) Lin(-) BM cells displayed vigorous chemotactic response to CCL25. Furthermore, RT-PCR analysis detects mRNA expression of CCR9 in the c-kit(+) Lin(-) BM cells. Thus, these results demonstrate that the CCL25-CCR9 pathway is essential for CP formation and the consequent appearance of IEL.

The MHC haplotype heterozygosity (H-2d/H-2z) acts as one major predisposing genetic element for autoimmune disease resembling systemic lupus erythematosus (SLE) in the F1 hybrid of NZB (H-2d) and NZW (H-2z) mice. To determine a possible role of mixed-haplotype A molecules, we introduced a transgene A beta z into H-2d/H-2d homozygous (NZB x NZW.H-2d)F1 mice, in which, compared with the original H-2d/H-2z heterozygotes, the incidence and titer of IgG anti-DNA antibodies, serum levels of nephritogenic retroviral gp70/anti-gp70 immune complexes (ICs) and the associated incidence of IC-type lupus nephritis were reduced. Evidence for the formation of mixed-haplotype A alpha d A beta z molecules in the transgenic mice was obtained by A beta z molecule expression on the cell surface of splenic B cells and macrophages, thymic epithelial cells and mature B cells in the bone marrow. A alpha d A beta z-restricted T cell clones showed good proliferative responses to spleen cells from the transgenic mice, to an extent much larger than seen in cells from the original (NZB x NZW)F1 mice, suggesting that the expression of functional A alpha d A beta z molecules on cells in transgenic mice is considerably high. Compared with findings in transgene-negative littermates and the original (NZB x NZW)F1 mice, the A beta z transgene to a greater extent promoted serum levels of IgM anti-double-stranded (ds) DNA antibodies and IgM anti-gp70/gp70 ICs in the transgenic mice. None the less, the production of IgG anti-dsDNA antibodies and IgG anti-gp70/gp70 ICs as well as the development of renal disease was markedly suppressed. Possible mechanisms of such effects of the transgene are discussed.