CCL28 induces mucosal homing of HIV-1-specific IgA-secreting plasma cells in mice immunized with HIV-1 virus-like particles.

Veronica Rainone,Francisco Veas,Klaus Überla,Manuela Nebuloni,Gregor Dubois,Vladimir Temchura,Daria Trabattoni,Mario Clerici,Eleonora Lauri,Alberto Clivio,Paul A Goepfert

doi:10.1371/journal.pone.0026979

Abstract

Mucosae-associated epithelial chemokine (MEC or CCL28) binds to CCR3 and CCR10 and recruits IgA-secreting plasma cells (IgA-ASCs) in the mucosal lamina propria. The ability of this chemokine to enhance migration of IgA-ASCs to mucosal sites was assessed in a mouse immunization model using HIV-1IIIB Virus-like particles (VLPs). Mice receiving either HIV-1IIIB VLPs alone, CCL28 alone, or the irrelevant CCL19 chemokine were used as controls. Results showed a significantly increased CCR3 and CCR10 expression on CD19+ splenocytes of HIV-1IIIB VPL-CCL28-treated mice. HIV-1 Env-specific IFN-γ, IL-4 and IL-5 production, total IgA, anti-Env IgA as well as gastro-intestinal mucosal IgA-secreting plasma cells were also significantly augmented in these mice. Notably, sera and vaginal secretions from HIV-1IIIB VLP-CCL28-treated mice exhibited an enhanced neutralizing activity against both a HIV-1/B-subtype laboratory strain and a heterologous HIV-1/C-subtype primary isolate. These data suggest that CCL28 could be useful in enhancing the IgA immune response that will likely play a pivotal role in prophylactic HIV vaccines.

Highlights

The development of prophylactic and therapeutic vaccines against mucosal infections still represents a challenge [1,2]
We further investigate the immunomodulatory effects of MEC/CCL28 in a mouse model using a primeboost strategy based on HIV-1IIIB-Virus-like particles (VLPs) in the presence/absence of the murine chemokine gene inserted into a CpG-free expression vector
The CCL19-expressing plasmid was used as a negative control. This chemokine was chosen because, to CCL28, it plays a crucial role in lymphoid cell trafficking but it does not have an effect on IgA+ plasma cells; CCL19 does not bind CCR3 or CCR10 but rather uses CCR7

Summary

Introduction

The development of prophylactic and therapeutic vaccines against mucosal infections still represents a challenge [1,2]. IgA-secreting plasma blasts and plasma cells (IgA-ASCs) are characterized by a number of surface receptor proteins, including CCR3 and CCR10, which are bound by specific chemokines [6,7]. Both CCR3 and CCR10 bind CCL28, a CC chemokine known as Mucosae-associated Epithelial Chemokine, or MEC [6,8,9,10]. These interactions are involved in both migration and recruitment of IgA-ASCs into mucosal lamina propria (MLP) [4,10,11]. CCL28 is widely expressed in epithelial tissues of various mucosal sites and it chemoattracts IgA-ASCs originated from mucosal lymphoid organs in mucosal effector sites, including the large and small intestine, bronchi, the mammary as well as salivary glands in both mice and humans [4]

Methods

Results

Conclusion