Certain regulatory lymphocyte subpopulations like regulatory T cells can suppress T cell expansion by granzyme B (GrB) secretion. Recently, we found that B cells can also produce GrB and acquire regulatory potential in response to interleukin (IL-)21. Since HIV is associated with elevated serum IL-21 levels, we hypothesized that GrB-expressing B cells may be induced during HIV infection. Here, we show that infection of CD4+ T cells with HIV 1 (NL4-3) induces strong expression of IL-21 without upregulation of CD40 ligand. We demonstrate that such IL-21+CD40Llow T cells secrete IL-21, thereby inducing GrB in cocultured B cells rather than supporting plasma cell differentiation. In line with these results, serum levels of both IL-21 and GrB are significantly higher in HIV-infected patients before HAART as compared to healthy controls. Up to 60% of freshly isolated B cells from HIV-infected patients, but not healthy control B cells, express GrB. Of note, coculture of HIV-infected CD4+ T cells with GrB+ B cells results in GrB transfer, and strongly suppresses both T cell proliferation and viral replication as indicated by significantly reduced p24 levels. The observed effects are enhanced by IL-21, and reduced by GrB inhibition. In summary, GrB induction in HIV-specific B cells may play a role in decelerating expansion of HIV-infected CD4+ T cells, while interfering with their terminal differentiation into plasma cells.
- Copyright © 2013 by The American Association of Immunologists, Inc.