The mucosae-associated epithelial chemokine (MEC/CCL28) modulates immunity in HIV infection.

Eleonora Castelletti,Alberto Clivio,Daria Trabattoni,Francesco Mazzotta,Manuela Nebuloni,Mario Clerici,Chipepo Kankasa,Sergio Lo Caputo,Louise Kuhn,Luca Piacentini,Moses Sinkala,Johanna Gajardo,Grace M Aldrovandi,Eleonora Lauri,Dorothy H Bray,Francisco Veas,Manuela Borelli,Donald M Thea,Douglas Nixon

doi:10.1371/journal.pone.0000969

Abstract

BackgroundCCL28 (MEC) binds to CCR3 and CCR10 and recruits IgA-secreting plasma cells (IgA-ASC) in the mucosal lamina propria (MLP). Mucosal HIV-specific IgA are detected in HIV-infection and exposure. The CCL28 circuit was analyzed in HIV-infected and-exposed individuals and in HIV-unexposed controls; the effect of CCL28 administration on gastrointestinal MLP IgA-ASC was verified in a mouse model.Methodology/FindingsCCL28 was augmented in breast milk (BM) plasma and saliva of HIV-infected and –exposed individuals; CCR3+ and CCR10+ B lymphocytes were increased in these same individuals. Additionally: 1) CCL28 concentration in BM was associated with longer survival in HIV vertically-infected children; and 2) gastro-intestinal mucosal IgA-ASC were significantly increased in VSV-immunized mice receiving CCL28.ConclusionsCCL28 mediates mucosal immunity in HIV exposure and infection. CCL28-including constructs should be considered in mucosal vaccines to prevent HIV infection of the gastro-intestinal MLP via modulation of IgA-ASC.

Highlights

Migration of IgA-secreting plasma cells into the mucosal lamina propria (MLP) was recently shown to be correlated with specific chemokines and chemokine receptors [1,2,3,4,5,6,7,8,9,10,11,12,13]
These chemotactic abilities are limited to IgA-expressing plasma blasts and plasma cells (IgA-ASC) as the migration of neither IgM nor IgG ASC is stimulated by the CCL28-CCR10/CCR3 or the CCL25-CCR9 systems [1,2,3,4,5,6,7,8,9,10,11,12,13]
CCL28 has a potent antimicrobial activity directed toward both Gram-positive and Gram-negative microorganisms [3]. This chemokine is expressed by bone marrow stromal cells, suggesting that the interaction of CCL28 with CCR10+/CCR3+ B cells may contribute to the integration between the mucosal and the systemic immune responses [3]

Summary

Introduction

Migration of IgA-secreting plasma cells into the mucosal lamina propria (MLP) was recently shown to be correlated with specific chemokines and chemokine receptors [1,2,3,4,5,6,7,8,9,10,11,12,13]. It has been shown that CCR9 ligates the CC chemokine CCL25 ( known as thymus-expressed chemokine, or TECK) [4,10], whereas both CCR10 and CCR3 bind a second CC chemokine named CCL28 ( known as mucosae-associated epithelial chemokine, or MEC) [1,5,10,12] These interactions induce the migration and the recruitment of IgA-ASC in the MLP. CCL28 has a potent antimicrobial activity directed toward both Gram-positive and Gram-negative microorganisms [3] This chemokine is expressed by bone marrow stromal cells, suggesting that the interaction of CCL28 with CCR10+/CCR3+ B cells may contribute to the integration between the mucosal and the systemic immune responses [3]. CCL28-including constructs should be considered in mucosal vaccines to prevent HIV infection of the gastro-intestinal MLP via modulation of IgA-ASC

Methods

Results

Conclusion