(B)
(B). with functional CXCL12-chemotaxis under the herein used conditions. In summary, our results show that HCMV designs mDC adhesion to compromise migration toward CCL19, but retaining CXCL12 responsiveness. Thus, we hypothesize that a favored migration pattern toward the bone marrow, but not to secondary lymphoid organs, could ultimately cause a failure in the induction of potent antiviral immune responses. pattern acknowledgement receptors, antigen MMP3 uptake, or specific pro-inflammatory cytokines (5). These maturing DCs upregulate the expression of MHC PC786 I and II as well as of costimulatory molecules (6). Furthermore, the chemokine receptors CCR7 and CXCR4 are highly expressed on mature DCs (mDCs) (7C10). CXCR4 binds the widely expressed chemokine CXCL12 (SDF-1), homing the cell, e.g., to the bone marrow where the highest expression is found (11, 12). In contrast, CCR7 responds to the chemokines CCL19 and CCL21, highly expressed in secondary lymphoid organs (SLOs), directing mDCs to SLOs for T cell activation (13, 14). Leukocytes and especially DCs are very motile cells circulating through different tissues and lymphoid organs. In general, migration requires multiple changes in cytoskeleton architecture and cellCsubstrate interactions (15), regulated, e.g., by chemokine belief and signaling with rearrangement of the cytoskeleton and modulation of adhesion (16C18). Integrins are heterodimeric transmembrane receptors that mediate adhesion and comprise a very high diversity by the combination of – and -chains resulting in 24 users in mammalia, all possessing different ligands and binding affinities (19). Leukocytes express integrins of the 1-, 2-, 3- and 7-families, while 2- and 7-integrins are restricted to these cells (20). The 2-integrins consist of the -subunit cluster of differentiation (CD) 18 that associates with one of the four different -chains to form LFA-1 (CD11a/CD18 or L2), Mac-1 or CR3 (CD11b/CD18 or M2), p150.95 (CD11c/CD18 or X2) and D2 (CD11d/CD18) (21, 22). Expression of the latter ones is restricted to specific leukocyte subsets, while LFA-1 is usually constitutively expressed on all leukocytes, thus playing essential roles in controlling adhesion and cellular interactions (21, 23C25). Like all other integrins, LFA-1 dynamically switches between its active and inactive conformation, mediated by outside-in and inside-out signaling (19, 26). Only two proteins talin and cytohesin-1 are currently known to modulate LFA-1 activity by direct binding to its cytoplasmic CD18 tail (27). Interestingly, the latter one was reported to be specific for 2-integrins and to be predominantly expressed in hematopoietic cells (28, 29). Cytohesin-1 interacting protein (CYTIP), a direct interactor of cytohesin-1, is usually expressed by hematopoietic cells and upregulated during DC maturation (30C32). One important function of CYTIP is usually to abrogate cytohesin-1-induced activation of LFA-1. Cytohesin-1 directly PC786 interacts with membrane associated phosphatidylinositol-3,4,5-trisphosphate (PIP3), produced by phosphoinositide 3-kinase (33), and PC786 the intracellular CD18 domain name of LFA-1 resulting in increased LFA-1 affinity, promoting adhesion to its ligands (28, 29, 34). CYTIP reverses these interactions by binding to cytohesin-1, with subsequent translocation PC786 of the cytohesin-1/CYTIP-complex to the cytosol, thereby diminishing LFA-1 affinity and ultimately adhesion (30). The -herpesvirus human cytomegalovirus (HCMV) exhibits seroprevalences of 45% up to almost 100% depending on age, gender and socioeconomic situation (35). While the main contamination of healthy adult individuals is usually subclinical, infections of immune-immature fetus or neonates as well as immunocompromised patients frequently prospects to severe symptoms with high morbidity and mortality (36). Permissive target cells for HCMV replication are fibroblasts,.