Chemokines and chemokine receptors during viral infections in man

Abstract

Chemokines and chemokine receptors are critical mediators of cell migration during immune surveillance, inflammation and development. The generation of antibody responses depends on B and T cell collaboration within germinal centers in lymphoid tissue. Activation of B lymphocytes is accompanied by alternations in chemokine responsiveness that brings together the antigen specific B cells with its cognate CD4 T cell. Several human viral infections have been shown to interfere with chemokine receptor expression and signaling, I have studied two human viruses. Human immunodeficiency virus-1 (HIV-1) infects mainly CD4+ T cells but infection is associated with impaired B cell function with loss of B cell responses to specific antigens and a loss of B cells with memory phenotype. Epstein-Barr virus (EBV) in contrary infects mainly B cells and is associated with a variety of human malignancies.

The aim of this thesis was to i) characterize chemokine receptor expression on different subpopulations of B cells during chronic HIV-1 infection and primary EBV infection; ii) study the effects of altered receptor expression on B cell migration during HIV-1 and EBV infection and iii) clarify the role of CXCL12 for proliferation and signaling in childhood pre-B ALL.

Our main finding in paper I was a decreased expression of CXCR5 both at the mRNA and protein level on B cells from HIV-1 infected individuals compared to controls. We could also detect an increase in CXCL13 expression in B cells from HIV-1 infected subjects. In paper II and III, tonsillar B cells were infected with EBV and the expression of CXCR4, CXCR5 and CCR7 was followed over time. Already two days after infection, a decrease of surface CXCR4, CXCR5 and CCR7 was detected and after 14 day of infection both CXCR4, CXCR5 and CCR7 was totally absent from the cell surface. EBV infection also caused a decrease in migration towards the respective ligands compared to uninfected B cells.

In order to further investigate the CXCR4/CXCL12 pathway in pre B leukemic cells, we found that CXCL12 enhances proliferation of ALL cells and signal transducer and activators 5 (STAT5) was activated upon ligation with CXCL12 (paper IV). CXCL12 has together with interleukin-7 (IL-7) been shown to enhance proliferation of leukemic cells and we could detect a higher IL-7 level in a few children with pre-B ALL compared to controls. Interestingly, in paper V, we showed that IL-7Rα is down-regulated on T cells in HIV-1 infected individuals and this correlated with depletion of CD4+ T cells in HIV-1 infected subjects.

In summary, little is known about the impact of chemokines and chemokine receptors during viral infection and how it modulates the immune response. In these studies, I have shown that both HIV-1 and EBV influences B cell chemokine receptor expression and migration during infection in humans. The natural evolution of our work would be to study how chemokine and chemokine receptors affect the natural course of infection and evolution of immunological responses in experimental models of the viruses used in this thesis, e.g. HIV-1 and EBV.