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- Freland, Sofia
(författare)
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Lymphoid development and function in MHC class I deficient mice
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- MHC class I molecules present short peptide fragments, derived from proteins synthesized in the cytosol, to specific CTL. The MHC class I molecule is a heterotrimer encompassed of a polymorphic transmembrane glycoprotein (heavy chain), ß2-microglobulin (ß2m), and a peptide. In the first study (Paper I), we carried out an in-depth analysis with respect to the requirement of the ß2m and TAP transported peptides for proper MHC class I assembly, and intracellular transport. We show that properly conformed class I heavy chains can be detected in a terminally glycosylated form indicative of cell surface expression in H-2b, H-2d and H-2s ß2m -/- ConA-stimulated splenocytes incubated at reduced temperature. Furthermore, we demonstrate the presence of Kb molecules at the surface of ß2m -/- cells cultured at 37° C. We provide evidence for a role of peptide in intracellular transport of free MHC class I heavy chains, through analysis of ConA-stimulated splenocytes from TAP1 -/-, ß2m -/- double mutant TAP1/ß2m -/- mice. Studies of MHC class I-deficient mice have also provided insights into the role of MHC class I molecules in the development of CD8+ T lymphocytes and NK cells. Although ß2m -/- mice were initially thought to be devoid of MHC class I molecules and CD8+ T cells, it is now clear that they express low levels of MHC class I molecules on the cell surface, and studies by others have provided evidence for the selection of a small pool of CD8+ T cells in these mice. The latter is true also for TAP1 -/- as well as for TAP1/ Min -/- mice. In Paper II, we addressed the ability of TAP1 -/-, ß2m -/- and TAP1/ ß2m -/- mice to mount responses against allogeneic and syngeneic MHC class I-positive tumor grafts, and against MHC class I-deficient tumor grafts. The results demonstrated a potent ability of TAP1 -/-, ß2m -/- as well as TAP1/ Win -/- mice to reject allogeneic tumors. In contrast to published data, rejection of syngeneic MHC class I expressing tumors was also observed. This response was specific for the MHC class I deficient mice. Finally, MHC class I deficient tumor grafts were accepted in MHC class I deficient mice while similar grafts were rejected in wild type mice. To directly address the potential role of CD8+ T cell responses in ß2m -/- mice, we introduced a CD8 null mutation into ß2m -/- mice (Paper III). ß2m/CD8 -/- mice and corresponding control mice were primed, and challenged with syngeneic tumor grafts. While ß2m -/- mice readily cleared such tumor grafts, similar tumor grafts grew progressively in a dose dependent manner in ß2m/CD8 -/- mice. This study provided formal proof for the dependence of CD8+ T cells in the tumor rejection responses studied. The present results suggest that studies using ß2m -/- as a model of CD8+ T cell deficiency must be regarded with caution. NK cells recognize MHC class I molecules with specific receptors. In the mouse, MHC class I-specific inhibitory receptors are dimeric C-type lectins that belong to the Ly49 family. In an attempt to re-express a functional ß2m gene in ß2m -/- mice, we generated a panel of founder mice with an unexpected mosaic expression of MHC class I molecules (Paper IV). This allowed us to study lymphocyte development in an environment where MHC class I-positive and -negative cells had co-evolved, and to examine of the influence of MHC class I on the expression of the Ly49C inhibitory receptor on NK cells. This receptor binds to H-2Kb. It is expressed at low levels on NK cells in wild type mice of the H-2b haplotype, but at markedly higher levels on NK cells in ß2m -/- mice and other strains of mice lacking expression of H-2Kb. Through the analysis of the present MHC class I mosaic mice, we demonstrate that the expression levels of Ly49C on NK cells are a consequence not only of MHC class I expression in the environment, but also of the expression of MHC class I molecules by the NK cells themselves.
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- Svensson-Arvelund, Judit, 1982-, et al.
(författare)
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Decidual macrophages contribute to the unique leukocyte composition at the fetal-maternal interface by production of IL-35, induction of Treg cells and production of homeostatic chemokines
- 2015
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Reproductive success depends on the ability of the maternal immune system to adapt in order to tolerate and support the growing semi-allogenic fetus. Macrophages, being a major leukocyte population in the uterine mucosa (decidua), may play a central role in promoting the unique composition and regulatory phenotype of leukocytes that is characteristic for the fetal-maternal interface. We show that decidual macrophages display a predominantly immune regulatory gene profile and produce the immunosuppressive cytokine IL-35 but no other members of the IL-12 family (IL-12, IL-23 and IL-27). Decidual macrophages also promoted the selective expansion of CD25highFoxp3+ Tregs but not of Tbet+ Th1, GATA-3+ Th2 and Rorγt+ Th17 cells. In addition, these macrophages preferentially secreted the monocyte- and Treg-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. Among in vitro macrophages, distinct chemokine profiles were observed; IL-4/13 upregulated Th2-associated chemokines (CCL17, CCL22, CCL26) while LPS/IFNγ upregulated Th1-associated chemokines (CXCL9, CXCL10, CXCL11, CCL5). M(IL-10) macrophages (induced by M-CSF and IL-10) showed a chemokine profile similar to that of decidual macrophages, as shown by gene expression and protein analysis. By using M(IL-10) macrophages as a model of decidual macrophages, we show that these cells promote the recruitment of CD14+ monocytes, while migration of several lymphocyte populations was unaltered or prevented. These data implicate decidual macrophages as critical regulators of the decidual leukocyte composition and phenotype that is associated with successful reproduction.
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