Delayed but enhanced

The constitutively expressed chemokines CCL21 (formerly SLC) and CCL19 (ELC) share a common receptor, CCR7, that is expressed on all naïve T cells, B cells and activated dendritic cells (DCs). Receptor occupancy stimulates chemotaxis and activation of leukocyte integrins. Paucity of lymph node T cell (Plt) mice do not express the chemokines CCL21 and CCL19 and consequently have defective migration of naïve T cells and activated DCs into the T cell zones of lymphoid organs. In the Journal of Experimental Medicine, Mori et al. investigated whether Plt mice have defects in T cell immune responses. Although it was thought that these mice would be unable to develop primary T cell responses, it was found that T cell responses to contact sensitization and subcutaneous immunization are delayed but ultimately enhanced compared to wild-type mice. Interestingly, antigen-specific immune responses in the lymph nodes and spleen of Plt mice do not decline after reaching their peak and instead remain elevated for at least 8 weeks. The results suggest that activation of T cells in within T-dependent areas of secondary lymphoid organs may be required for diminishing the immune response.

J. Exp. Med. 193, 207–218 (2001)

CXCL12-dependent stem cells

Homing of hematopoietic stem cells to the bone marrow (BM), their retention and repopulation is critical for the establishment of hematopoiesis. CXCL12 (formerly SDF-1) controls stem cell trafficking and development. However, the regulation of CXCL12 and the identity of CXCL12-producing cells in the BM were unclear. In the Journal of Clinical Investigation, Ponomaryov et al. show that immature osteoblasts and endothelial cells produce the bulk of CXCL12 in vitro and in vivo. Successful stem cell transplantation requires pretreatment with radiation or other DNA-damaging agents. Conditioning of mice with these agents increased CXCL12 expression and correlated well with an increase in homing, survival and proliferation of transplanted human stem cells. Thus, stem cell homing, retention and repopulation is dependent on CXCL12 production by immature osteoblasts and endothelial cells.

J. Clin. Invest. 106, 1331–1339 (2000) 

Triggering integrins

Leukocyte recruitment from blood is a vital event in the regulation of immune responses. Activated integrins play a critical role in stabilizing the interaction of circulating leukocytes with the vessels. In Immunity, Constantin et al. show that the chemokines CCL21 (formerly SLC), CCL19 (formerly ELC) and CXCL12 (formerly SDF-1) rapidly induce a high-affinity state of the β2-integrin LFA-1. These chemokines stimulate LFA-1 lateral mobility on the plasma membrane leading to very rapid localization to clusters and large polar patches. A phosphatidyl inositol-3 kinase–dependent signaling pathway controls the lateral mobility but not induction of the high-affinity state. The study also shows that lateral mobility and induction of high-affinity state of LFA-1 can play a cooperative role in mediating rapid lymphocyte arrest under physiological conditions.

Immunity 13, 759–769 (2000) 

Trafficking to solid organs

Chemokines play an essential role in concentrating immune cells into functional compartments within lymphoid organs. However, the role of chemokines in organizing cells into compartments in nonlymphoid tissues is not well established. In the Journal of Experimental Medicine, Yoneyama et al. analyzed the recruitment and roles of dendritic cell (DC) precursors into Propionibacterium acnes–induced granulomas in mouse liver. During infection, precursor DC migration to the perisinusoidal space was dependent on CCL3 (formerly MIP-1α). After migration, the DCs matured within the granulomas and migrated to the portal tract-associated lymphoid tissue (PALT) where they interacted with T cells. Migration of mature DCs to the PALT was CCL21 (formerly SLC)-dependent. Anti-CCL21 reduced PALT expansion and exacerbated granuloma formation. Thus, trafficking of DCs into solid organs like the liver is dependent on chemokines.

J. Exp. Med. 193, 1–15 (2001) 

Follicular B helper T cells

Chemokines and their receptors recruit and position leukocytes within specialized lymphoid compartments. In the Journal of Experimental Medicine, Breitfeld et al. and Schaerli et al. show that CXCR5 defines a distinct population of memory T cells localizing to follicles. These CXCR5+CD4+ T cells migrate in response to CXCL13, which is selectively expressed by reticular cells and blood vessels within B cell follicles. This directs CXCR5+ T cells to the B cell follicles where CD40 ligand, CD69, HLA-DR and ICOS is concomitantly expressed. CXCR5+ T cells cannot produce cytokines efficiently but can support the production of antibodies. In comparison, peripheral CXCR5+CD4+ T cells that coexpress CCR7 migrate weakly to chemokines and cannot induce antibody production. Thus, these CXCR5+CD4+ T cells represent a distinct memory T cell subset with B helper cell function.

J. Exp. Med. 192, 1545–1551 and J. Exp. Med. 192, 1553–1562 (2000)

CCL5 on atopy and asthma

Several genes are associated with asthma and atopy. The gene that encodes the chemokine CCL5 (formerly RANTES) is one such gene. The promoter region of the gene encoding CCL5 contains a single nucleotide polymorphism (G→A at position-403). In Genes and Immunity, Fryer et al. examined the role of the CCL5 polymorphism in the development of atopy and asthma. The -403 allele was associated with increased susceptibility to both asthma and atopy. The proportion of individuals carrying the mutant allele was higher in atopic, nonasthmatics and nonatopic asthmatics compared to normal controls. Interestingly, the mutant allele was associated with skin-test positivity to aeroallergen, not IgE expression, and the homozygosity of this allele was associated with increased risk of airway obstruction. Thus this preliminary data suggest that the association of CCL5 with asthma and atopy function though independent mechanisms.

Genes Immunity 1, 509–514 (2001)