Brucella abortusinduces intracellular retention of MHC-I molecules in human macrophages down-modulating cytotoxic CD8⁺T cell responses

Abstract

SummaryBrucella abortus elicits a vigorous Th1 immune response which activates cytotoxic T lymphocytes. However, B. abortus persists in its hosts in the presence of CD8 + T cells, establishing a chronic infection. Here, we report that B. abortus infection of human monocytes/macrophages inhibited the IFN-g-induced MHC-I cell surface expression. This phenomenon was dependent on metabolically active viable bacteria. MHC-I down-modulation correlated with the development of diminished CD8 + cytotoxic T cell response as evidenced by the reduced expression of the activation marker CD107a on CD8 + T lymphocytes and a diminished percentage of IFN-g-producing CD8+ T cells. Inhibition of MHC-I expression was not due to changes in protein synthesis. Rather, we observed that upon B. abortus infection MHC-I molecules were retained within the Golgi apparatus. Overall, these results describe a novel mechanism based on the intracellular sequestration of MHC-I molecules whereby B. abortus would avoid CD8 + cytotoxic T cell responses, evading their immunological surveillance.

Adrenal Steroids Modulate the Immune Response during Brucella abortus Infection by a Mechanism That Depends on the Regulation of Cytokine Production

“…In our laboratory, we demonstrated that B. abortus infection inhibits MHC-I and MHC-II expression induced by IFN-␥, contributing in this way to the chronicity of Brucella infection (43,44). Our results indicated that DHEA immune intervention could positively affect monocyte function, resulting in a significant recovery of the inhibited IFN-␥-induced MHC-I and -II expression mediated by B. abortus infection.…”

“…IFN-␥ has a critical role in protective immunity against Brucella (6, 7). The strategies that allow B. abortus to survive for prolonged periods inside macrophages could be explained at least in part by the inhibition of the IFN-␥-induced expression of MHC-I and MHC-II molecules (43,44). We hypothesized that this phenomenon could be modulated by cortisol and DHEA.…”

CD8 + T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection

“…Both cell-intrinsic (stunted IFN-␥ production and delayed increase in the number of IFN-␥-producing cells) and cell-extrinsic factors due to an environment of chronic infection were found to affect the ability of CD8 ϩ T cells to control chronic brucellosis. Current vaccine constructs do not generate a viable CD8 ϩ T cell immune response and moreover ignore CD8 ϩ T cell-mediated immunological memory because these cells have been considered unimportant in the control of human infection (34). An understanding of how to rescue exhausted CD8 ϩ T cells may be critical to decreasing the incidence of reactivation and reinfection, even after vaccination.…”

The quest for a true One Health perspective of brucellosis

“…Similarly, while CD8 T cells can be cytotoxic (in addition to producing IFN-γ) and such cytotoxic cells have been demonstrated to be generated in vivo following infection, a clear role for cytotoxic cells is not evident (29). Finally, infection of human macrophages resulted in decreased major histocompatibility complex (MHC) class I molecules on the surface, and thus decreased Brucella antigen presentation to CD8 T cells and decreased killing (32).…”