Human Peripheral Blood T Cells, Monocytes, and Macrophages Secrete Macrophage Inflammatory Proteins 1α and 1β following Stimulation with Heat-InactivatedBrucella abortus

Abstract

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-␥) 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 ␤-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 ␤-chemokines following stimulation with HBa, and this effect could not be blocked by anti-IFN-␥ neutralizing antibodies. Among purified T cells, macrophage inflammatory protein 1␣ and 1␤ (MIP-1␣ and MIP-1␤, respectively) secretion was observed primarily in human CD8؉ T cells. The kinetics of ␤-chemokine induction in T cells were slow (3 to 4 days). The majority of ␤-chemokine-producing CD8 ؉ T cells also produced IFN-␥ following HBa stimulation, as determined by triple-color intracellular staining. A significant number of CD8 ؉ T cells contained stored MIP-1␤ that was released after HBa stimulation. Both HBa and LPS-Ba stimulated high levels of MIP-1␣ and MIP-1␤ production in elutriated monocytes and even higher levels in macrophages. In these cells, ␤-chemokine mRNA was upregulated within 30 min and proteins were secreted within 4 h of stimulation. The monocyte-and macrophage-derived ␤-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.The discovery that several ␤-chemokines (i.e., macrophage inflammatory proteins 1␣ and 1␤ [MIP-1␣ and MIP-1␤, respectively] and RANTES) secreted by short-term human CD8 ϩ cell lines can effectively block infection of human peripheral blood mononuclear cells (PBMCs) with macrophage-

Heat-KilledBrucella abortusInduces TNF and IL-12p40 by Distinct MyD88-Dependent Pathways: TNF, Unlike IL-12p40 Secretion, Is Toll-Like Receptor 2 Dependent

“…We have shown that it can be used as an effective carrier for HIV-1 peptides and proteins to induce longterm Ab and CTL responses systemically and mucosally in mice and monkeys (13). B. abortus also induces ␤-chemokine secretion from human CD8 ϩ T cells and macrophages (32). Additionally, we have shown that B. abortus can induce mouse DC to migrate to T cell areas in the spleen, where they secrete IL-12 (30).…”

Diminished percentage of CD4+ T-lymphocytes expressing interleukine-2 receptor alpha in chronic brucellosis

“…23,24 Activated CD8C T-cells participate in protection against Brucella in humans, through cytotoxicity or/and by the production of IFNg. 9e11, 25 Human brucellosis studies have also demonstrated an increased percentage of CD8C T-lymphocytes in peripheral blood of patients chronically infected with Brucella spp. 26e28 In line with these studies, we found significantly higher percentage of CD8C T-lymphocytes in PHA-stimulated PBMC from chronic brucellosis patients.…”

Role of Toll-Like Receptor 4 in Induction of Cell-Mediated Immunity and Resistance toBrucella abortusInfection in Mice

“…These data confirm that Brucella S LPS is a more powerful adjuvant compared to R LPS not only to trigger innate but also adaptive immune responses. Recently, B. abortus LPS has been shown to induce relevant quantities of ␤-chemokines known to bind to the human immunodeficiency virus type 1 coreceptor CCR5 and block virus entry (60). Therefore, heat-inactivated B. abortus and its LPS have been proposed as carriers for therapeutic vaccines for individuals with human immunodeficiency virus (15).…”