Brucella abortus down‐regulates MHC class II by the IL‐6‐dependent inhibition of CIITA through the downmodulation of IFN regulatory factor‐1 (IRF‐1). Issue 3 (20th October 2016)

• Record Type: Journal Article
• Authors: Velásquez, Lis N.; Milillo, M. Ayelén; Delpino, M. Victoria; Trotta, Aldana; Fernández, Pablo; Pozner, Roberto G.; Lang, Roland; Balboa, Luciana; Giambartolomei, Guillermo H.; Barrionuevo, Paula
• Is Part Of: Journal of leukocyte biology. Volume 101:Issue 3(2017)
• Page Start: 759
• Page End: 773
• Publication Date: 2016-10-20
• Subjects: bacteria -- monocytes/macrophages -- host immunity -- immune‐evasion strategies; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.4A0416-196R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : Molecular mechanisms employed by B. abortus to inhibit MHC‐II surface expression, in order to evade host immunity and establish a chronic infection. Abstract : Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4 + T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN‐γ‐induced surface expression of MHC class II (MHC‐II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B. abortus is able to down‐regulate the expression of MHC‐II, remained to be elucidated. In this study, we demonstrated that B. abortus infection inhibits the IFN‐γ‐induced transcription of MHC‐II, transactivator (CIITA) and MHC‐II genes. Accordingly, we observed that the synthesis of MHC‐II proteins was also diminished. B. abortus was not only able to reduce the expression of mature MHC‐II, but it also inhibited the expression of invariant chain (Ii)‐associated immature MHC‐II molecules. Outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, diminished the expression of MHC‐II and CIITA transcripts to the same extent as B. abortus infection. IL‐6 contributes to these down‐regulatory phenomena. In addition, B. abortus and its lipoproteins, through IL‐6 secretion, induced the transcription of the negative regulators of IFN‐γ signaling, suppressor of cytokine signaling (SOCS)‐1 and ‐3, without interfering with STAT1 activation. Yet, B. abortus lipoproteins via IL‐6 inhibit the expression of IFN regulatory factor 1 (IRF‐1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that B. abortus inhibits the expression of MHC‐II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection.