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Infection and Immunity, June 2001, p. 3817-3826, Vol. 69, No. 6
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.6.3817-3826.2001

Human Peripheral Blood T Cells, Monocytes, and Macrophages Secrete Macrophage Inflammatory Proteins 1alpha and 1beta following Stimulation with Heat-Inactivated Brucella abortus

Marina Zaitseva,1 Lisa R. King,1 Jody Manischewitz,1 Michael Dougan,1 Lee Stevan,2 Hana Golding,1 and Basil Golding2,*

Division of Viral Products1 and Division of Hematology,2 Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Received 12 October 2000/Returned for modification 14 December 2000/Accepted 13 March 2001

Heat-killed Brucella abortus (HBa) has been proposed as a carrier for therapeutic vaccines for individuals with immunodeficiency, due to its abilities to induce interleukin-2 (IL-2) and gamma interferon (IFN-gamma ) in both CD4+ and CD8+ T cells and to upregulate antigen-presenting cell functions (including IL-12 production). In the current study, we investigated the ability of HBa or lipopolysaccharide isolated from HBa (LPS-Ba) to elicit beta -chemokines, known to bind to the human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and to block viral cell entry. It was found that human peripheral blood mononuclear cells secreted beta -chemokines following stimulation with HBa, and this effect could not be blocked by anti-IFN-gamma neutralizing antibodies. Among purified T cells, macrophage inflammatory protein 1alpha and 1beta (MIP-1alpha and MIP-1beta , respectively) secretion was observed primarily in human CD8+ T cells. The kinetics of beta -chemokine induction in T cells were slow (3 to 4 days). The majority of beta -chemokine-producing CD8+ T cells also produced IFN-gamma following HBa stimulation, as determined by triple-color intracellular staining. A significant number of CD8+ T cells contained stored MIP-1beta that was released after HBa stimulation. Both HBa and LPS-Ba stimulated high levels of MIP-1alpha and MIP-1beta production in elutriated monocytes and even higher levels in macrophages. In these cells, beta -chemokine mRNA was upregulated within 30 min and proteins were secreted within 4 h of stimulation. The monocyte- and macrophage-derived beta -chemokines were sufficient to block CCR5-dependent HIV-1 envelope-mediated cell fusion. These data suggest that, in addition to the ability of HBa to elicit antigen-specific humoral and cellular immune responses, HBa-conjugated HIV-1 proteins or peptides would also generate innate chemokines with antiviral activity that could limit local viral spread during vaccination in vivo.

* Corresponding author. Mailing address: Division of Hematology, Center for Biologics Evaluation and Research, FDA, HFM-345, Bldg. 29, Room 232, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 827-3017. Fax: (301) 402-2780. E-mail: Golding{at}CBER.FDA.GOV.

Infection and Immunity, June 2001, p. 3817-3826, Vol. 69, No. 6
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.6.3817-3826.2001


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