Chemokine receptor expression and modulation by Mycobacterium tuberculosis antigens on mononuclear cells from human lymphoid tissues

Abstract

SummaryChemokine receptor switching on lymphoid cells is an important factor regulating migration and homing, but little is known about the expression of such molecules during Mycobacterium tuberculosis infection in humans. We describe CCR2, CCR5 and CCR7 expression on human cells from blood, spleen and pulmonary hilar lymph nodes (PHLN) stimulated by M. tuberculosis antigens. CCR2 was not expressed by CD3 + cells regardless of the presence of antigen, but was highly expressed on CD14 + CD63 + monocytes/macrophages. CCR2 decreased on splenic monocytes/macrophages by nearly 50% in culture, independent of antigen, but remained high in blood and PHLN. CCR5 was low in CD3 + cells and was down-regulated by M. tuberculosis antigens on blood and splenic cells but not in PHLN. CCR5 was highly expressed on monocytes/macrophages and was down-regulated by M. tuberculosis antigens at 48 hr only in blood. Less than 15% of CD3 + cells from spleen and PHLN were CCR7 + , whereas nearly 40% from blood expressed this receptor on primary isolation. However, CCR7 in PHLN increased in culture, independent of antigen. Monocytes/macrophages did not express CCR7. Thus, we characterize, for the first time, chemokine receptor expression and differential modulation by M. tuberculosis antigens on human mononuclear cells from spleen, blood and PHLN. Knowledge of chemokine receptor switching in human lymphoid tissue provides novel insight into mechanisms of the immune response to M. tuberculosis with potential effects on directing cell trafficking.

Mycobacterium tuberculosisAntigens Specifically Modulate CCR2 and MCP-1/CCL2 on Lymphoid Cells from Human Pulmonary Hilar Lymph Nodes

“…High expression of CCR2 on monocytes and macrophages has been described in mice (19) and humans (42), and its expression on such cells from mediastinal human LN has been described previously only by our group (43). CCR2 presence on these cells and also its low levels on DC suggest a role for this receptor in APC migration, localization, and interaction with T cells within the LN, as suggested previously (20), and strengthen the concept of Randolph et al (41) that peripheral tissue monocytes that become DC readily migrate to the LN.…”

“…Discrepancy between these results may be due to the different origin of the cells, i.e., blood monocyte-derived macrophages/DC vs PHLN, or simply that APC from PHLN respond differently to Mtb than blood-derived cells. In this regard, we reported previously that human peripheral blood MNC are more likely to be affected by the modulatory effects of Mtb Ag than cells from spleen and PHLN (43,44).…”

Mycobacterium tuberculosisH37Rv is more effective compared to vaccine strains in modulating neutrophil functions: anin vitrostudy

“…This basal level of chemokine may not be sufficient to bind to CCR5 and downregulate its expression level; instead, it may act as a trigger for the monocytes to upregulate CCR5 expression. In another study, when mononuclear cells were stimulated with MTB antigen, CCR5 expression on monocytes was increased, but CCR7 was hardly detectable (Arias et al ., ). Interestingly, we observed increase in the expression of both the receptors on monocytes, supporting the fact that both CCR5‐ and CCR7‐mediated monocyte signaling functions occur with the help of neutrophils.…”

Mechanisms regulating chemokine receptor activity

“…31 Interestingly, chemokine receptor switch and modulation of mRNA expression has also been reported with Mycobacterium tuberculosis antigens and proposed to be part of a normal programme of cell co-ordination needed to contain infection. 32 Enhancing protein degradation independently of, or in combination with, a transcriptional control is also an efficient way to down-regulate chemokine receptor expression, as described for CXCR1 and CXCR2 on activated neutrophils or CCR2 during monocyte differentiation. 20,33 Significantly, changes in the regulation of chemokine receptor expression can contribute to pathological conditions such as Alzheimer's disease, where there is evidence for binding of the amyloid b protein to the receptor for advanced glycation end-products (RAGE) up-regulating CCR5 expression on brain endothelial cells causing T cell infiltration in the brain.…”