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B lymphocyte-induced maturation protein-1 contributes to intestinal mucosa homeostasis by limiting the number of IL-17-producing CD4+ T cells.

ABSTRACT: The transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) plays important roles in embryonic development and immunity. Blimp-1 is required for the differentiation of plasma cells, and mice with T cell-specific deletion of Blimp-1 (Blimp-1CKO mice) develop a fatal inflammatory response in the colon. Previous work demonstrated that lack of Blimp-1 in CD4(+) and CD8(+) T cells leads to intrinsic functional defects, but little is known about the functional role of Blimp-1 in regulating differentiation of Th cells in vivo and their contribution to the chronic intestinal inflammation observed in the Blimp1CKO mice. In this study, we show that Blimp-1 is required to restrain the production of the inflammatory cytokine IL-17 by Th cells in vivo. Blimp-1CKO mice have greater numbers of IL-17-producing TCR?(+)CD4(+)cells in lymphoid organs and in the intestinal mucosa. The increase in IL-17-producing cells was not restored to normal levels in wild-type and Blimp-1CKO-mixed bone marrow chimeric mice, suggesting an intrinsic role for Blimp-1 in constraining the production of IL-17 in vivo. The observation that Blimp-1-deficient CD4(+) T cells are more prone to differentiate into IL-17(+)/IFN-?(+) cells and cause severe colitis when transferred to Rag1-deficient mice provides further evidence that Blimp-1 represses IL-17 production. Analysis of Blimp-1 expression at the single cell level during Th differentiation reveals that Blimp-1 expression is induced in Th1 and Th2 but repressed by TGF-? in Th17 cells. Collectively, the results described here establish a new role for Blimp-1 in regulating IL-17 production in vivo.

SUBMITTER: Salehi S

PROVIDER: S-EPMC3529138 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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B lymphocyte-induced maturation protein-1 contributes to intestinal mucosa homeostasis by limiting the number of IL-17-producing CD4+ T cells.

Salehi Soofia S Bankoti Rashmi R Benevides Luciana L Willen Jessica J Couse Michael M Silva Joao S JS Dhall Deepti D Meffre Eric E Targan Stephan S Martins Gislâine A GA

Journal of immunology (Baltimore, Md. : 1950) 20121116 12

The transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) plays important roles in embryonic development and immunity. Blimp-1 is required for the differentiation of plasma cells, and mice with T cell-specific deletion of Blimp-1 (Blimp-1CKO mice) develop a fatal inflammatory response in the colon. Previous work demonstrated that lack of Blimp-1 in CD4(+) and CD8(+) T cells leads to intrinsic functional defects, but little is known about the functional role of Blimp-1 in regul ...[more]

PMID: 23162130

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Project description:BACKGROUND: The regulation of adult stem cell migration through human hematopoietic tissue involves the chemokine CXCL12 (SDF-1) and its receptor CXCR4 (CD184). In addition, human leukocyte elastase (HLE) plays a key role. When HLE is located on the cell surface (HLE(CS)), it acts not as a proteinase, but as a receptor for ?(1)proteinase inhibitor (?(1)PI, ?(1)antitrypsin, SerpinA1). Binding of ?(1)PI to HLE(CS) forms a motogenic complex. We previously demonstrated that ?(1)PI deficiency attends HIV-1 disease and that ?(1)PI augmentation produces increased numbers of immunocompetent circulating CD4(+) lymphocytes. Herein we investigated the mechanism underlying the ?(1)PI deficiency that attends HIV-1 infection. METHODS AND FINDINGS: Active ?(1)PI in HIV-1 subjects (median 17 µM, n?=?35) was significantly below normal (median 36 µM, p<0.001, n?=?30). In HIV-1 uninfected subjects, CD4(+) lymphocytes were correlated with the combined factors ?(1)PI, HLE(CS) (+) lymphocytes, and CXCR4(+) lymphocytes (r(2)?=?0.91, p<0.001, n?=?30), but not CXCL12. In contrast, in HIV-1 subjects with >220 CD4 cells/µl, CD4(+) lymphocytes were correlated solely with active ?(1)PI (r(2)?=?0.93, p<0.0001, n?=?26). The monoclonal anti-HIV-1 gp120 antibody 3F5 present in HIV-1 patient blood is shown to bind and inactivate human ?(1)PI. Chimpanzee ?(1)PI differs from human ?(1)PI by a single amino acid within the 3F5-binding epitope. Unlike human ?(1)PI, chimpanzee ?(1)PI did not bind 3F5 or become depleted following HIV-1 challenge, consistent with the normal CD4(+) lymphocyte levels and benign syndrome of HIV-1 infected chimpanzees. The presence of IgG-?(1)PI immune complexes correlated with decreased CD4(+) lymphocytes in HIV-1 subjects. CONCLUSIONS: This report identifies an autoimmune component of HIV-1 disease that can be overcome therapeutically. Importantly, results identify an achievable vaccine modification with the novel objective to protect against AIDS as opposed to the current objective to protect against HIV-1 infection.

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B lymphocyte-induced maturation protein-1 contributes to intestinal mucosa homeostasis by limiting the number of IL-17-producing CD4+ T cells.

Publications

B lymphocyte-induced maturation protein-1 contributes to intestinal mucosa homeostasis by limiting the number of IL-17-producing CD4+ T cells.

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