TH1-polarized immune responses, which confer protection against intracellular pathogens, are thought to be initiated by dendritic cells (DCs) that enter lymph nodes from peripheral tissues. We found following viral infection or immunization, inflammatory monocytes were recruited into lymph nodes directly from the blood to become CD11c+CD11bhiGr-1+ inflammatory DCs, which produced abundant interleukin 12(p70) and potently stimulated TH1 responses. This monocyte extravasation required CCR2 but not CCL2 or CCR7. Thus, inflammatory DC accumulation and TH1 responses were markedly reduced in Ccr2−/−mice, preserved in Ccl2−/− mice, and relatively increased in CCL19-CCL21-Ser-deficient plt mutant mice, in which all other lymph node DC types were reduced. We conclude that blood-derived inflammatory DCs play a major role in the development of TH1 immune responses.

The function of the Fanconi anemia group C protein (FANCC) is still unknown, though many studies point to a role in damage response signaling. Unlike other known FA proteins, FANCC is mainly localized to the cytoplasm and is thought to act as a messenger of cellular damage rather than an effector of repair. FANCC has been shown to interact with several cytoplasmic and nuclear proteins and to delay the onset of apoptosis through redox regulation of GSTP1. We investigated the fate and function of FANCC during apoptosis. Here we show that FANCC undergoes proteolytic modification by a caspase into a predominant 47-kDa ubiquitinated protein fragment. Lack of proteolytic modification at the putative cleavage site delays apoptosis but does not affect MMC complementation. These results suggest that FANCC function is regulated through proteolytic processing.Fanconi anemia (FA) 1 is a genetic disease identified as a bone marrow failure syndrome associated with cancer susceptibility, congenital defects, and cellular sensitivity to DNA cross-linking agents (1). FA patients are distributed into at least nine complementation groups. Eight FA genes have been cloned, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, and FANCL, and recently the breast cancer susceptibility gene, BRCA2, has been assigned to complementation group D1 and possibly to group B, although the latter requires confirmation (2-11). Since a defect in any of the nine possible FA genes leads to a similar clinical phenotype, FA proteins appear to act in a common pathway to the breast cancer susceptibility proteins BRCA1 and BRCA2 sequentially and/or as a multiprotein complex.Several studies have shown that five of eight known FA proteins, FANCA, FANCC, FANCE, FANCF, and FANCG, bind to each other and form a multiprotein complex that translocates to the nucleus (12-18). Assembly of the multiprotein complex seems to be necessary for the activation through posttranslational monoubiquitination of FANCD2 (19,20). Monoubiquitination of FANCD2 is dependent on the recently identified FANCL gene that possesses ubiquitin ligase activity (11). The FANCD2 protein has been associated in nuclear foci with BRCA1, suggesting that BRCA1 may be a downstream component of the FA molecular pathway. Recently, the BRCA1 protein was shown to interact with the FANCA protein supporting a role of BRCA1 in the Fanconi pathway (21).The FA group D1 protein, BRCA2/FANCD1/FANCB, may function upstream in the pathway by promoting the formation of the FA complex and/or downstream by transducing signals from FA proteins to the DNA repair machinery. Mutation in one of the FA genes abolishes the FA complex formation, the monoubiquitination of FANCD2 and the nuclear foci formation in response to genotoxic stress. Nuclear localization of the FA complex was found to be critical for cellular resistance to MMC (17,22). However, several lines of investigation have suggested additional extranuclear functions for at least some FA components. For instance, FANCC and FANCG were shown to bind non-nuclear protein...

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