The positive effects of IL-7 on survival and homeostatic proliferation of T cells might be severely impaired in HIV-infected individuals due to IL-7Ralpha down-regulation. Differentiation towards a CD28-negative memory phenotype in response to chronic activation may lead to an overall decrease of IL-7 mediated survival within the peripheral T-cell pool.
IntroductionHIV-1 infection is associated with extensive B-cell abnormalities, manifested by phenotypic alterations and polyclonal B-cell activation, increased frequencies of B-cell malignancies, hypergammaglobulinemia, as well as poor antigen-specific immune responses to recall and de novo antigens. [1][2][3][4][5] In secondary lymphoid tissue, HIV-1 infection induces follicular hyperplasia and alterations in the architecture of germinal center (GC) 6 and splenic marginal zones. 7 Defects in the B-cell compartment become overt already during primary HIV-1 infection 8 as measured by a decline of B-cell number, increased expression of activation, and apoptosis markers. 9 The mechanisms by which HIV-1 impairs humoral immunity may be the result of intrinsic B-cell defects and/or a lack of functional dialogue between B and T cells in secondary lymphoid organs.Lymphocyte migration and recirculation between the periphery and lymphoid tissue are critical for effective immunity and are in part regulated by chemokine receptors on lymphocytes together with the expression of their respective ligands (chemokines) in different tissue compartments. 10,11 In recent years, increasing attention has been given to the potential role of viruses to interfere with chemokine receptor expression, binding, and signaling. [12][13][14] In this respect, HIV-1 has been extensively studied because the virus uses CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5) as coreceptors for entry into target cells, in addition to the main receptor, the CD4 molecule. 15 However, the expression of chemokine receptors in the context of B-cell trafficking is still poorly studied in chronic HIV-1 infection.The chemokine receptor CXCR4 is broadly expressed on a majority of B cells in the bone marrow (BM), as well as in the periphery, and plays an important role for early B-cell development 16,17 and plasma cell homing to the BM. 18,19 On the other hand, CXCR5 is expressed by mature B cells and contributes to the recruitment of naive B cells into the lymph nodes 20 where the GC reaction occurs with class switch, somatic hypermutation, and affinity maturation. The microanatomic organization of GCs into light and dark zones has been attributed to the expression of CXCR4 and CXCR5. 21,22 B cells also express a moderate amount of CCR7, which contributes to the migration within the lymph node. 23 In the present study, we examined the cell surface expression of chemokine receptors CXCR4, CXCR5, and CCR7 on B cells isolated from the blood of HIV-1-infected patients because these receptors mediate important events of B-cell homing to lymphoid tissue. 20,[23][24][25][26] Using gene expression profiling of chemokine receptors and chemokines, we found a high level of CXC chemokine ligand 13 (CXCL13) mRNA in B cells from HIV-1-infected patients compared with controls; in addition, these cells secreted a high level of the CXCL13 protein after in vitro activation. Histopathology studies performed in lymphoid tissues revealed the presence of CXCL13 ϩ B cel...
SummaryChemokines and chemokine receptors are likely to play important roles in the pathogenesis of Epstein-Barr virus (EBV) -associated disease. The primary EBV infection occurs in the oropharynx where the virus infects mainly tonsillar B cells. We have previously shown that CXCR4 expression on tonsillar B cells is modulated by EBV. Here, CXCR5 and CCR7 expression, which is important for migration into lymphoid tissue, was followed for 14 days after EBV infection of tonsillar B cells. Early after infection (2 days) there were only minor changes in CXCR5 and CCR7 expression. However, at day 7 the expression of CXCR5, as well as of CCR7, was decreased and by day 14 these molecules were no longer present at the cell surface. Furthermore, EBV infection affects the chemotactic response to CXCL13 and CCL21 (the ligands for CXCR5 and CCR7, respectively) with a reduction of ligand-induced migration at day 2. Using gene expression profiling, we identified an additional set of chemokines and chemokine receptors that were changed upon EBV infection in comparison with non-infected tonsillar B cells. In particular, messenger RNA expression for CCR9 and the complement receptor C5AR1 was increased. Both receptors mediate homing to mucosal tissue. The alterations of the expression of these molecules may lead to retention of EBV-infected tonsillar B cells in the interfollicular region of the tonsil.
Summary The primary Epstein–Barr virus (EBV) infection occurs in the oropharynx, where the virus infects B cells and subsequently establishes latency in the memory B‐cell compartment. EBV has previously been shown to induce changes in the cell surface expression of several chemokine receptors in cell lines and the transfection of EBNA2 or LMP1 into a B‐cell‐lymphoma‐derived cell line decreased the expression of CXCR4. We show that in vitro EBV infection reduces the expression of CXCR4 on primary tonsil B cells already 43 hr after infection. Furthermore, EBV infection affects the chemotactic response to stromal cell‐derived factor (SDF‐1)α/CXCL12, the ligand for CXCR4, with a reduction of SDF‐1α‐induced migration. To clarify whether this reduced migration is EBV‐specific or a consequence of cell activation, tonsillar B cells were either infected with EBV, activated with anti‐CD40 and interleukin‐4 (IL‐4) or kept in medium. Activation by anti‐CD40 and IL‐4 decreased the CXCR4 expression but the CD40 + IL‐4‐stimulated cells showed no reduction of chemotactic efficacy. Our finding suggests that changing the SDF‐1α response of the EBV‐infected B cells may serve the viral strategy by directing the infected cells into the extrafollicular areas, rather than retaining them in the lymphoepithelium.
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