Major histocompatibility class II (MHC-II) molecules are transmembrane proteins that have a central role in development and control of the immune system. They are encoded by a multigene family and their expression is tightly regulated. MHC-II deficiency (OMIM 209920) is an autosomal recessive immunodeficiency syndrome resulting from defects in trans-acting factors essential for transcription of MHC-II genes. There are four genetic complementation groups (A, B, C and D), reflecting the existence of four MHC-II regulators. The factors defective in groups A (CIITA), C (RFX5) and D (RFXAP) have been identified. CIITA is a non-DNA-binding co-activator that controls the cell-type specificity and inducibility of MHC-II expression. RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters. Mutations in the genes encoding RFX5 (RFX5) or RFXAP (RFXAP) abolish binding of RFX (refs 7,8,12). Similar to groups C and D, group B is characterized by a defect in RFX binding, and although it accounts for the majority of patients, the factor defective in group B has remained unknown. We report here the isolation of RFX by a novel single-step DNA-affinity purification approach and the identification of RFXANK, the gene encoding a third subunit of RFX. RFXANK restores MHC-II expression in cell lines from patients in group B and is mutated in these patients. RFXANK contains a protein-protein interaction region consisting of three ankyrin repeats. Its interaction with RFX5 and RFXAP is essential for binding of the RFX complex to MHC-II promoters.

Cell surface expression of major histocompatibility complex class II (MHCII) molecules is increased during the maturation of dendritic cells (DCs). This enhances their ability to present antigen and activate naive CD4+ T cells. In contrast to increased cell surface MHCII expression, de novo biosynthesis of MHCII mRNA is turned off during DC maturation. We show here that this is due to a remarkably rapid reduction in the synthesis of class II transactivator (CIITA) mRNA and protein. This reduction in CIITA expression occurs in human monocyte-derived DCs and mouse bone marrow–derived DCs, and is triggered by a variety of different maturation stimuli, including lipopolysaccharide, tumor necrosis factor α, CD40 ligand, interferon α, and infection with Salmonella typhimurium or Sendai virus. It is also observed in vivo in splenic DCs in acute myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalitis. The arrest in CIITA expression is the result of a transcriptional inactivation of the MHC2TA gene. This is mediated by a global repression mechanism implicating histone deacetylation over a large domain spanning the entire MHC2TA regulatory region.

Increasing evidence suggests that neutrophils may participate in the regulation of adaptive immune responses, and can reach draining lymph nodes and crossprime naive T cells. The aim of this study was to identify the mechanism(s) involved in the migration of neutrophils to the draining lymph nodes. We demonstrate that a subpopulation of human and mouse neutrophils express CCR7. CCR7 is rapidly expressed at the membrane upon stimulation. In vitro, stimulated human neutrophils migrate in response to the CCR7 ligands CCL19 and CCL21. In vivo, injection of complete Freund adjuvant induces a rapid recruitment of neutrophils to the lymph nodes in wild-type mice but not in Ccr7 ؊/؊ mice. Moreover, intradermally injected interleukin-17-and granulocyte-macrophage colonystimulating factor-stimulated neutrophils from wild-type mice, but not from Ccr7 ؊/؊ mice, migrate to the draining lymph nodes. These results identify CCR7 as a chemokine receptor involved in the migration of neutrophils to the lymph nodes. IntroductionPolymorphonuclear neutrophils are the most abundant immune cells in human blood (60% of leukocytes). Every day, 10 11 neutrophils transit through the adult human circulation. 1 They are the first type of leukocytes recruited at the site of infection, where they represent the major infiltrating cells. Their migration and subsequent activation are controlled by chemokines and cytokines such as chemokine (C-X-C motif) ligand 8 (CXCL8) and tumor necrosis factor-␣ (TNF-␣). At the inflammatory site, microorganisms are phagocytosed by neutrophils, destroyed via oxygendependent or oxygen-independent mechanisms, or sequestered in extracellular traps. 1,2 Neutrophils also contain an important arsenal of microbicidal mediators. 3 Neutrophils are short-lived, terminally differentiated cells that have long been considered to be the prototypic innate immune cells and to have a restricted number of properties. 4,5 Nevertheless, recent studies have shown that the biologic properties of neutrophils are more complicated than was previously thought. Neutrophils exhibit characteristic features classically dedicated to professional antigen-presenting cells. 6,7 Under certain circumstances, neutrophils display a dendritic cell (DC)-like phenotype, as evidenced by the expression of the DC markers CD83, CD80, CD86, and major histocompatibility complex II (MHC-II) molecules. Neutrophils may present antigens in an MHC-II-dependent manner and induce the proliferation of antigen-specific T cells. [6][7][8] More recently, we reported that neutrophils cross-prime naive CD8 ϩ T lymphocytes. 9 Finally, neutrophils may also influence the polarization of antigen-specific T-cell responses. [10][11][12] Interestingly, previous studies have reported that, after the capture of antigens in the periphery, neutrophils may migrate to the lymph nodes. [13][14][15] In a murine model of Toxoplasma gondii infection, parasites are transported by neutrophils from the infection site to draining lymph nodes. 15 Similarly, after an injection of ovalbumin (O...

In vivo, a wild-type pattern of major histocompatibility complex (MHC) class II expression requires a locus control region (LCR). Whereas the role of promoter-proximal MHC class II regulatory sequences is well established, the function of the distal LCR remained obscure. We show here that this LCR is bound by the MHC class II-specific transactivators regulatory factor X (RFX) and class II transactivator (CIITA). Binding of these factors induces long-range histone acetylation, RNA polymerase II recruitment and the synthesis of extragenic transcripts within the LCR. The finding that RFX and CIITA regulate the function of the MHC class II LCR reveals an unexpected degree of complexity in the mechanisms controlling MHC class II gene expression.