Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN- -induced class II transactivator

ABSTRACT After a primary infection, human cytomegalovirus (HCMV) establishes lifelong latency in myeloid lineage cells, and the virus has developed several mechanisms to avoid immune recognition and destruction of infected cells. In this study, we show that HCMV utilizes two different strategies to reduce the constitutive expression of HLA-DR, -DP, and -DQ on infected macrophages and that infected macrophages are unable to stimulate a specific CD4+ T-cell response. Downregulation of the HLA class II molecules was observed in 90% of the donor samples and occurred in two phases: at an early (1 day postinfection [dpi]) time point postinfection and at a late (4 dpi) time point postinfection. The early inhibition of HLA class II expression and antigen presentation was not dependent on active virus replication, since UV-inactivated virus induced downregulation of HLA-DR and inhibition of T-cell proliferation at 1 dpi. In contrast, the late effect required virus replication and was dependent on the expression of the HCMV unique short (US) genes US1 to -9 or US11 in 77% of the samples. HCMV-treated macrophages were completely devoid of T-cell stimulation capacity at 1 and 4 dpi. However, while downregulation of HLA class II expression was rather mild, a 66 to 90% reduction in proliferative T-cell response was observed. This discrepancy was due to undefined soluble factors produced in HCMV-infected cell cultures, which did not include interleukin-10 and transforming growth factor β1. These results suggest that HCMV reduces expression of HLA class II molecules on HCMV-infected macrophages and inhibits T-cell proliferation by different distinct pathways.

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Species specificity and augmentation of responses to class II major histocompatibility complex molecules in human CD4 transgenic mice.

Journal of Experimental Medicine ◽

10.1084/jem.175.6.1707 ◽

1992 ◽

Vol 175 (6) ◽

pp. 1707-1715 ◽

Cited By ~ 25

Author(s):

E Barzaga-Gilbert ◽

D Grass ◽

S K Lawrance ◽

P A Peterson ◽

E Lacy ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

Class Ii ◽

T Cell Proliferation ◽

Human Class ◽

Cell Responses ◽

Histocompatibility Complex ◽

Species Specific

Murine T cell responses to human class II major histocompatibility complex (MHC) molecules were shown to be a minimum of 20-70-fold lower than responses to allogeneic molecules. Transgenic mice expressing slightly below normal (75-95%) or very high (250-380%) cell surface levels of human CD4 were utilized to determine whether this was due to a species-specific interaction between murine CD4 and class II molecules. Human CD4 was shown to function in signal transduction events in murine T cells based on the ability of anti-human CD4 antibody to synergize with suboptimal doses of anti-murine CD3 antibody in stimulating T cell proliferation. In mice expressing lower levels of human CD4, T cell responses to human class II molecules were enhanced up to threefold, whereas allogeneic responses were unaltered. In mice expressing high levels of human CD4, responses to human class II molecules were enhanced at least 10-fold, whereas allogeneic responses were between one and three times the level of normal responses. The relatively greater enhancement of the response to human class II molecules in both lines argues for a preferential interaction between human CD4 and human class II molecules. In mice expressing lower levels of human CD4, responses to human class II molecules were blocked by antibodies to CD4 of either species, indicating participation by both molecules. In mice expressing high levels of human CD4, responses to both human and murine class II molecules were almost completely blocked with anti-human CD4 antibody, whereas anti-murine CD4 antibody had no effect. However, anti-murine CD4 continued to synergize with anti-CD3 in stimulating T cell proliferation in these mice. Thus, overexpression of human CD4 selectively impaired the ability of murine CD4 to assist in the process of antigen recognition. The ability of human CD4 to support a strong allogeneic response under these conditions indicates that this molecule can interact with murine class II molecules to a significant extent. Despite the fact that human CD4 appeared to be the only functional coreceptor in these mice, responses to human class II molecules were still much lower than those to murine class II alloantigens. This indicates that species-specific interactions between class II molecules and CD4 expressed on peripheral T cells are not sufficient to account for the low xenogeneic response and that intrinsic differences in T cell receptor structures or the need for species specificity in the interaction between CD4 and class II molecules during positive selection are also important.

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Superantigenic Staphylococcal Exotoxins Induce T-Cell Proliferation in the Presence of Langerhans Cells or Class II–Bearing Keratinocytes and Stimulate Keratinocytes to Produce T-Cell–Activating Cytokines

Journal of Investigative Dermatology ◽

10.1111/1523-1747.ep12371727 ◽

1994 ◽

Vol 102 (1) ◽

pp. 31-38 ◽

Cited By ~ 71

Author(s):

Yoshiki Tokura ◽

Junji Yagi ◽

Junji Mark O'Malley ◽

Julia M. Lewis ◽

Masahiro Takigawa ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Langerhans Cells ◽

Class Ii ◽

T Cell Proliferation

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DQ 65–79, A Peptide Derived from HLA Class II, Mimics p21 to Block T Cell Proliferation

The Journal of Immunology ◽

10.4049/jimmunol.171.10.5064 ◽

2003 ◽

Vol 171 (10) ◽

pp. 5064-5070 ◽

Cited By ~ 10

Author(s):

Chen Dong ◽

Shu-Chen Lyu ◽

Alan M. Krensky ◽

Carol Clayberger

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Class Ii ◽

Hla Class Ii ◽

T Cell Proliferation

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Immunogenic and Protective Potential of Mutans Streptococcal Glucosyltransferase Peptide Constructs Selected by Major Histocompatibility Complex Class II Allele Binding

Infection and Immunity ◽

10.1128/iai.01582-06 ◽

2006 ◽

Vol 75 (2) ◽

pp. 915-923 ◽

Cited By ~ 15

Author(s):

S. Culshaw ◽

K. LaRosa ◽

H. Tolani ◽

X. Han ◽

J. W. Eastcott ◽

...

Keyword(s):

Cell Proliferation ◽

Major Histocompatibility Complex ◽

T Cell ◽

Dental Caries ◽

Functional Significance ◽

Class Ii ◽

Binding Activity ◽

T Cell Proliferation ◽

Major Histocompatibility ◽

Histocompatibility Complex

ABSTRACT Mutans streptococcal glucosyltransferases (GTF) have been demonstrated to be effective components of dental caries vaccines. We had previously selected peptide subunits of GTF for vaccine development based on putative functional significance and conservation of GTF primary structure among enzyme isoforms. In this study, 20 20-mer linear GTF peptides were synthesized, 17 identified on the basis of the highest potential major histocompatibility complex (MHC) class II-binding activity using computer-generated algorithms (Epimatrix and ProPred) and 3 with previously demonstrated functional significance. The immunoreactivities of these peptides were explored with rodent systems. Sera from GTF-immunized rats, assessed for binding to linear peptides by enzyme-linked immunosorbent assay, demonstrated immunoglobulin G antibody reactivity with peptides 6 and 11 and a T-cell proliferation response to peptides 6, 9, 11, and 16. Multiple antigenic peptide (MAP) constructs were synthesized from promising linear sequences. Rats that were immunized with MAP 7, 11, or 16, respectively, responded well to the immunizing MAP. Most importantly, a robust immune response (antibody and T-cell proliferation) was observed to native GTF following MAP 11 (amino acids 847 to 866; VVINNDKFVSWGITDFEM) immunization. This response inhibited GTF enzyme function. Two dental caries pathogenesis experiments were performed wherein rats were immunized with MAP constructs 11, 16, and/or 11 plus 16, followed by infection with cariogenic Streptococcus sobrinus. In both experiments cariogenic bacterial recoveries were reduced relative to total streptococci in the MAP 11- and MAP 11 plus 16-immunized groups, and the extent of dental caries was also significantly reduced in these groups. Thus, we have identified a peptide with projected avid MHC-binding activity that elicited immunoreactivity with native GTF and demonstrated protection against dental caries infection after immunization, implying that this peptide may be important in a subunit dental caries vaccine.

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