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Immune cells in pregnant uterine mucosa: functional properties, cellular composition and tissue organization
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
1993 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pregnant uterus mucosa - decidua - is an "immunologically privileged" site. A semiallogeneic embryo is allowed to survive, develop, and grow while the same tissue implanted outside the uterus will be rejected. The decidua basalis, which participates in the placenta formation, is a tissue rich in lymphoid cells. We have studied decidua associated mononuclear cells (DMC) from normal early pregnancies in humans. The cells were investigated with respect to surface marker profiles, ultrastructure, organization in the tissue, and functional properties. In addition, we have studied the expression of receptors for the iron-binding protein lactoferrin on these cells, and characterized the receptor (Lf-R).

Ten to fiftee percent of all cells in decidua belong to the lymphoid cell lineage. They are present in aggregates [lymphoid cell clusters (LCC) mainly located in the vicinity of decidual/endometrial glands] and as individual cells, intra- or subepithelially along the glands (IEL) , and in the stroma. The LCC appear to be centres of immune reactivity. They occur at a frequency of 0.40.2/mm2 tissue and are composed of different population of activated T cells and NK cells in close contact with each other. Interestingly, B cells are not present in the LCC. DMC consist of four major lymphocyte subpopulation of similar sizes: TCRγδ+/CD56+cells, TCRγδ+/CD56-cells, TCRγδ-/CD56+cells and TCRαβ+/CD8+cells. TCRαβ+/CD4+ cells and monocytes are also present. Most DMC have long, thick processes, microvilli, and cytoplasmic granules. They are in intimate contact with surrounding lymphoid, epithelial and stromal cells. Signs of cellular movement and excretion of granules are also seen.

About half of the T cells are TCRαβ cells. These cells lack CD4 and CD8. A large fraction of them are CD56+, a rare phenotype at other sites. Most of the TCRγδ+ cells express activation/memory markers (CD45RO, the Kp43 antigen, transferrin receptor, and MHC class II antigens), and many cells express the mucosa homing receptor HML-1. Morphologically these cells either display features characteristic for cytotoxic cells or contain unique nuclear inclusions.

More than half of TCRαβ cells are CD8+, but CD4+ cells are also found. These cells also display activation markers.

DMC use both transferrin and lactoferrin for their iron supply. The Lf-R on activated lymphocytes appears to be made of two peptides of 47 and 65 kD MW.

Freshly isolated DMC respond poorly or not at all to activation through the TCR/CD3 complex, probably due to the low surface density of the complex. However, the TCR/CD3 complex can be up-regulated by stimulation with PMA/Ionomycin in vitro, suggesting that the lymphocytes are suppressed in vivo. Glandular epithelial cells produce immunosuppressive factor(s) that act on CD8+, TCRγδ+, and CD56+ cells. The proximity between the LCC and the glands indicates that this factor(s) may play a role in local immunosuppression. The identity of the factor(s) is presently unknown. The cytokine mRNA profile of DMC, as determined by RT-PCR, reveals IFN-γ, IL-8 and TGF-β1 mRNA in all samples, and IL-1β, IL-2, IL-10, TNF-α and GM-CSF mRNA in some samples. The cytokine profile is compatible with down-regulation of CTL activity.

The demands on the immune system in pregnant uterus mucosa are unique. On one hand, a genetically incompatible fetus must be accepted, the development of the placenta must be allowed, and the uteral mucosal tissue must be remodelled. On the other hand, the invasiveness of the trophoblast must be controlled, and the fetomaternal unit must be protected against infections. Our studies indicate that this is achieved through a highly regulated process involving different types of activated lymphoid cells interacting with each other and with glandular epithelial cells.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 1993. , 65 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 384
Keyword [en]
immunologically privileged site, TCR+γδ cells, CD56+ cells, large granular lymphocytes, immunosuppression, cytokine, interleukin, lymphoid cell cluster, intraepithelial lymphocytes, glandular epithelium, immuno electron microscopy, pregnancy, decidua, lactoferrin, lactoferrin receptor, colostrum
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-73398ISBN: 91-7174-808-3 (print)OAI: oai:DiVA.org:umu-73398DiVA: diva2:631372
Public defence
1993-09-17, Föreläsningssalen, Institutionen för mikrobiologi, Umeå universitet, Umeå, 09:30 (English)
Opponent
Supervisors
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved
List of papers
1. Human decidual leukocytes from early pregnancy contain high numbers of gamma delta+ cells and show selective down-regulation of alloreactivity.
Open this publication in new window or tab >>Human decidual leukocytes from early pregnancy contain high numbers of gamma delta+ cells and show selective down-regulation of alloreactivity.
1992 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 149, no 6, 2203-11 p.Article in journal (Refereed) Published
Abstract [en]

The mononuclear lymphoid cell population in human pregnant uterus mucosa, decidua, from early normal pregnancies was studied phenotypically and functionally. The phenotype was determined in situ by immunohistochemistry, and in isolated decidual mononuclear cell preparations by immunofluorescence and flow cytometry. A mild isolation procedure of gentle mechanical disruption followed by density gradient centrifugation was used. Leukocytes comprised a large part of the decidual tissue. They were present in aggregates mainly situated adjacent to the glandular epithelium. In addition, individual leukocytes were present intraepithelially, as well as scattered between the stromal cells and around vessels and lacunes. Four lymphocyte populations of approximately the same size were identified: TCR gamma delta+/CD56+ cells, TCR gamma delta+/CD56- cells, TCR gamma delta-/CD56+ cells, and TCR alpha beta+/CD8+ cells. TCR gamma delta- expressing cells comprised about 60% of the T cells. They were CD4-/CD8-, and about half of the TCR gamma delta+ cells expressed the memory/activation marker CD45RO. The Kp 43 Ag, earlier described on activated CD56+ and TCR gamma delta+ cells in peripheral blood, was essentially only expressed on the TCR gamma delta-/CD56+ cell population in decidua. At least 50% of the TCR alpha beta+ cells were CD8+. The function(s) of either one of these populations might be to prevent immunologic reactions against the fetus, to protect the uterus from unwanted extensive invasion of trophoblasts, or to protect the uteroplacental unit from infection. Decidual T cells did not respond to stimulation by alloantigens or mitogenic anti-CD3 mAb but responded to the same extent as PBMC to mitogenic lectins. The surface density of the TCR/CD3 complex was low on freshly isolated decidual lymphocytes, but could be up-regulated upon stimulation with PMA/Ionomycin. Local selective down-regulation of surface expression of the TCR/CD3 complex and of activation involving this complex might be one of the mechanisms by which a maternal immunologic reaction against the semiallogeneic fetus is prevented.

National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-67891 (URN)1381400 (PubMedID)
Available from: 2013-04-07 Created: 2013-04-07 Last updated: 2017-12-06
2. Immunomorphologic studies of human decidua-associated lymphoid cells in normal early pregnancy.
Open this publication in new window or tab >>Immunomorphologic studies of human decidua-associated lymphoid cells in normal early pregnancy.
Show others...
1994 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 152, no 4, 2020-32 p.Article in journal (Refereed) Published
Abstract [en]

Human decidual lymphocytes from early, normal pregnancy were characterized in situ with respect to ultrastructure and distribution of subsets. The ultrastructure of isolated decidual gamma delta T cells was also studied. CD45+ cells comprised 11 +/- 2% of all decidual cells. The majority were localized in large lymphoid cell clusters (LCC), near endometrial glands, or as intraepithelial lymphocytes (IEL) in glandular epithelium. The major cell populations in LCC were CD56+TCR-gamma delta+ cells, CD56+ cells, TCR-alpha beta+CD4+ cells, and TCR-alpha beta+CD8+ cells. All expressed activation markers (CD45RO, Kp43, and/or HML-1) and MHC class II Ag (HLA-DR, HLA-DP, and/or HLA-DQ). No B cells were found. Almost all IEL were activated TCR-gamma delta+ cells (CD56+ and CD56-). The glandular epithelial cells expressed heat shock protein 60 at the basolateral side facing the TCR-gamma delta+ IEL. Decidual lymphocytes displayed cytoplasmic processes, microvilli, characteristic cytoplasmic granules, and had intimate contact with neighboring cells. Lymphocytes in the outer rim of LCC and the stroma showed signs of cellular movement. Two main morphotypes of gamma delta T cells could be distinguished. One had single microvilli, membrane-bound granules, and nuclear inclusions. The other had many microvilli, nonmembrane-bound granules and cytoplasmic multivesicular bodies. Our data suggest that LCC are centers of immune reactivity where T and NK cells become activated. The activated cells may guard against infections and undue trophoblast invasion and/or be involved in modulating the local maternal immune system toward unresponsiveness against the semiallogeneic fetus.

National Category
Immunology Cell Biology
Identifiers
urn:nbn:se:umu:diva-67894 (URN)7509833 (PubMedID)
Available from: 2013-04-07 Created: 2013-04-07 Last updated: 2017-12-06
3. Immunomodulatory role of decidual epithelial cells in early human pregnancy
Open this publication in new window or tab >>Immunomodulatory role of decidual epithelial cells in early human pregnancy
(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-73396 (URN)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved
4. Activated human gamma delta T lymphocytes express functional lactoferrin receptors.
Open this publication in new window or tab >>Activated human gamma delta T lymphocytes express functional lactoferrin receptors.
1997 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 46, no 6, 609-18 p.Article in journal (Refereed) Published
Abstract [en]

Lactoferrin (Lf), an iron-binding protein in milk, mucosal secretions and neutrophil granules has bactericidal properties and is a source of iron for breast-fed infants. In this paper the authors show that most in vivo activated lymphocytes, i.e. freshly isolated lymphocytes from first trimester human decidua, and most in vitro activated human blood lymphocytes, express lactoferrin receptors (Lf-R), while unstimulated blood lymphocytes do not. All major lymphocyte subsets, i.e. alpha beta T cells, gamma delta T cells, CD8+ T cells, CD4+ T cells, B cells and NK cells, express Lf-R after activation. The proportion of Lf-R expressing activated gamma delta T cells is significantly larger than that of activated alpha beta T cells. Lf-R and transferrin receptors (Tr-R/CD71) show the same kinetics of appearance on activated blood lymphocytes and are, to a large extent, expressed on the same cells. However, 35% of decidual lymphocytes and 15% of activated blood lymphocytes express Lf-R only. Addition of Lf to cultures containing an optimal concentration of Tr augments the proliferative response to polyclonal T cell activators and alloantigens, suggesting that presently used standard culture conditions for in vitro activation are suboptimal in particular for gamma delta T cells. Lf-R on decidual lymphocytes contain bound Lf, which probably is produced locally. The results suggest that Lf is a growth-supporting factor, especially important in local immune responses in the mucosa.

National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-68017 (URN)9420625 (PubMedID)
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2017-12-06
5. Human milk contains proteins that stimulate and suppress T lymphocyte proliferation.
Open this publication in new window or tab >>Human milk contains proteins that stimulate and suppress T lymphocyte proliferation.
1990 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 79, no 3, 463-9 p.Article in journal (Refereed) Published
Abstract [en]

The modulatory effect of human milk proteins from colostrum and late milk on the proliferative response of human T lymphocytes activated by mitogens (OKT3 and leucoagglutinin from Phaseolus vulgaris) and alloantigens was studied. High concentrations (10-100 micrograms/ml) of crude colostral milk proteins had an inhibitory effect on T cell growth while low concentrations (0.1-1 microgram/ml) enhanced T cells growth. In contrast, proteins from late milk did not inhibit T lymphocyte proliferation while the enhancing effect was retained. Colostrum was fractionated by ammonium sulphate precipitation and gel filtration on sepharose 6B. The inhibitory activity was recovered in a protein fraction containing lactoferrin as its major component. Lactoferrin was, however, not responsible for the observed inhibition. On the contrary, lactoferrin in most cases augmented the proliferative response induced by polyclonal activators. The inhibitory activity was found to bind concanavalin A-sepharose suggesting an association with glycoprotein. Inhibitory fractions contained glycoproteins of the following molecular sizes 26, 74/76 (doublet), 84, 145 and 160 kD under reducing conditions. The inhibitory effect appeared to be lymphocyte specific since the active fraction did not inhibit the growth of tissue culture cells (HeLa cells and human fibroblasts) or bacteria. Furthermore, the fraction was not toxic for lymphocytes. The inhibitory colostrum factor may prevent the newborn from overreacting immunologically against the environmental antigens encountered at birth.

Keyword
inflammatory-bowel-disease; soluble fas ligand; t-cells; ulcerative-colitis; celiac-disease; crohns-disease; regional specialization; immune-system; human gut; expression
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-67888 (URN)2317950 (PubMedID)
Available from: 2013-04-07 Created: 2013-04-07 Last updated: 2017-12-06

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