Residual expression of functional MHC class II molecules in twin brothers with MHC class II deficiency is cell type specific

Wolf, Hermann M.; Thon, Vojtěch; Gulle, Heinz; Lechleitner, Sonja; Eibl, Martha M.; Petzelbauer, Peter

doi:10.1046/j.1365-2141.2001.03105.x

Cited by 9 publications

(3 citation statements)

References 51 publications

(80 reference statements)

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“…Even though MHC class II-dependent presentation by DC was not completely lost after infection, DC from K98-infected mice induced a stronger T. cruzi-specific T-cell response than those from RA-infected mice. The fact that DC from RA-infected mice can still elicit a noticeable T-cell response even with low MHC class II expression is not unexpected because it has been proved that only small amounts of MHC class II are necessary to mount a functional cellular response in vivo (39).…”

Section: Discussionmentioning

confidence: 99%

Trypanosoma cruziInfection Modulates In Vivo Expression of Major Histocompatibility Complex Class II Molecules on Antigen-Presenting Cells and T-Cell Stimulatory Activity of Dendritic Cells in a Strain-Dependent Manner

et al. 2003

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A striking feature of Chagas' disease is the diversity of clinical presentations. Such variability may be due to the heterogeneity among Trypanosoma cruzi isolates or to the host immune response. Employing two strains which differ in their virulence, we investigated the effect of in vivo infection on professional antigen-presenting cells (APC). Acute infection with the virulent RA strain downregulated the expression of major histocompatibility complex (MHC) class II on splenic dendritic cells (DC) and inhibited its induction on peritoneal macrophages and splenic B cells. It also impaired the ability of DC to prime allogeneic T cells and to form homotypic clusters, suggesting a low maturation state of these cells. In contrast, the low-virulence K98 strain maintained the expression of MHC class II on DC or stimulated it on peritoneal macrophages and B cells and preserved DC's T-cell priming capacity and homotypic clustering. DC from RA-infected mice elicited a lower activation of T. cruzi-specific T-cell proliferation than those from K98-infected mice. APC from RA-infected mice that reached the chronic phase of infection restored MHC class II levels to those found in K98-infected mice and upregulated costimulatory molecules expression, suggesting that the immunosuppression caused by this strain is only transient. Taken together, the results indicate that in vivo infection with T. cruzi modulates APC functionality and that this is accomplished in a strain-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Trypanosoma cruziInfection Modulates In Vivo Expression of Major Histocompatibility Complex Class II Molecules on Antigen-Presenting Cells and T-Cell Stimulatory Activity of Dendritic Cells in a Strain-Dependent Manner

et al. 2003

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“…However, transiently recovered CD4 T cells may at least contribute to immune functions that belong to innate immunity and/or class I MHC-restricted responses. Moreover, certain BLS patients are known to express class II MHC molecules in a cell type-specific manner (36,39), in which CD4 T cells recovered by anti-TCR Ab may persist and recognize peptide-Ags presented by class II MHC molecules. Furthermore, the administration of anti-TCR Ab would be far easier and widely available than bone marrow transplantation.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Treatment of Class II MHC-Deficient Mice with Anti-TCR Antibody Restores the Generation of Circulating CD4 T Cells and Optimal Architecture of Thymic Medulla

Nasreen

Ueno

Saito

et al. 2003

The Journal of Immunology

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TCR ligation by the self-peptide-associated MHC molecules is essential for T cell development in the thymus, so that class II MHC-deficient mice do not generate CD4+CD8− T cells. The present results show that the administration of anti-TCR mAb into class II MHC-deficient mice restores the generation of CD4+CD8− T cells in vivo. The CD4 T cells were recovered in the thymus, peripheral blood, and the spleen, indicating that the anti-TCR treatment is sufficient for peripheral supply of newly generated CD4 T cells. Unlike peripheral CD4 T cells that disappeared within 5 wk after the treatment, CD4+CD8− thymocytes remained undiminished even after 5 wk, suggesting that CD4 T cells in the thymus are maintained separately from circulating CD4 T cells and even without class II MHC molecules. It was also found that the mass of medullary region in the thymus, which was reduced in class II MHC-deficient mice, was restored by the anti-TCR administration, suggesting that the medulla for CD4+CD8− thymocytes is formed independently of the medulla for CD4−CD8+ thymocytes. These results indicate that in vivo anti-TCR treatment in class II MHC-deficient mice restores the generation of circulating CD4 T cells and optimal formation of the medulla in the thymus, suggesting that anti-TCR Ab may be useful for clinical treatment of class II MHC deficiencies.

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“…26,68 In particular, significant levels of HLA-DR expression could be detected on monocyte-derived DCs and epidermal Langerhans cells but not B cells or monocytes of twin brothers with RFX5 deficiency. 69,70 However, compared with other patients with RFX5 deficiency, these twin brothers presented with a rather mild disease phenotype, indicating that differences in the type of RFX5 mutation may influence residual MHCII expression. Patient-derived B-cell lines failed to up-regulate MHCII upon IFN␥ stimulation, 71,72 but since IFN␥-induced MHCII expression depends on the action of CIITA and indirectly the RFX complex 21 other stimuli should be tested in addition.…”

Section: Implications For Treatment Of Bare Lymphocyte Syndromementioning

confidence: 99%

MHC class II expression through a hitherto unknown pathway supports T helper cell-dependent immune responses: implications for MHC class II deficiency

Buch

Polić

Clausen

et al. 2006

Blood

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IntroductionMHC class II (MHCII) molecules play a pivotal role in the development of protective T-cell immunity by displaying antigenic peptides from the endocytic pathway to CD4 ϩ T helper (Th) cells. 1 MHCII gene expression is tightly regulated and mostly restricted to thymic epithelium 2,3 and professional antigenpresenting cells (APCs) [4][5][6] but inducible also in other cell types. Coordinated expression of all MHCII genes is controlled by a conserved promoter region. 7,8 This promoter contains the socalled X, X2, and Y boxes, which bind the heterotrimeric RFX complex 9 consisting of RFX5, RFXAP, and RFXANK, 10-13 CREB (cAMP-responsive element-binding protein), [14][15][16] and NF-Y. 17 Transcriptional activity of MHCII genes is, however, not only dependent on these DNA-binding molecules but requires the cell type-specific 18,19 or inducible presence 20,21 of the transcriptional coactivator CIITA. 22 Defects in one of the genes of the RFX proteins or CIITA led to almost complete absence of MHCII expression. This phenomenon was first observed in a human hereditary immunodeficiency, called MHCII deficiency or bare lymphocyte syndrome (BLS). 5,23,24 BLS patients have reduced Th-cell numbers and are extremely susceptible to infections with bacterial, viral, and fungal pathogens. 25 The development of Th-cell-dependent class-switched immunoglobulin responses is impaired in these patients, despite reports of residual MHCII expression on B-cell lines from some patients and the presence of CD4 ϩ T cells. 26,27 It seems unlikely that the Th cells of BLS patients develop in the thymus since the thymic cortex, which is normally responsible for positive selection, showed no MHCII expression in BLS patients. [28][29][30] To date, the only available treatment for this fatal disease is allogeneic BM transplantation (BMT), which in the case of BLS has a low success rate. 27,31 To further investigate the mechanisms underlying this immunodeficiency and to test novel treatment strategies, we and others have generated mouse models of BLS by inactivating the genes coding for CIITA and for RFX5. [32][33][34][35] Similar to the human disease, CIITA Ϫ/Ϫ and RFX5 Ϫ/Ϫ mice lack MHCII expression on the majority of peripheral APCs. Unexpectedly, residual MHCII expression was found in the thymic medulla, on a subset of dendritic cells (DCs) in peripheral lymphoid organs, and on in vitro-activated RFX5 Ϫ/Ϫ B cells. Due to the absence of MHCII in thymic cortex, both mutants are unable to generate Th cells and thus fail to mount Th-cell-dependent immune responses. [32][33][34] To test whether the residual MHCII expression in RFX5 Ϫ/Ϫ and CIITA Ϫ/Ϫ mice ("BLS mice"), and potentially also in Patients, materials, and methods Mouse maintenance and typingRFX5 Ϫ/Ϫ mice 33 and CIITA Ϫ/Ϫ mice 32 were on a mixed 129/Ola/C57BL/6 or 129/Sv/C57BL/6 background, respectively, and were intercrossed to generate CR Ϫ/Ϫ mice. The double knock out was confirmed by polymerase chain reaction (PCR) and Southern blot. For the RFX5 deficiency, the primers RFX...

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Residual expression of functional MHC class II molecules in twin brothers with MHC class II deficiency is cell type specific

Cited by 9 publications

References 51 publications

Trypanosoma cruziInfection Modulates In Vivo Expression of Major Histocompatibility Complex Class II Molecules on Antigen-Presenting Cells and T-Cell Stimulatory Activity of Dendritic Cells in a Strain-Dependent Manner

Trypanosoma cruziInfection Modulates In Vivo Expression of Major Histocompatibility Complex Class II Molecules on Antigen-Presenting Cells and T-Cell Stimulatory Activity of Dendritic Cells in a Strain-Dependent Manner

In Vivo Treatment of Class II MHC-Deficient Mice with Anti-TCR Antibody Restores the Generation of Circulating CD4 T Cells and Optimal Architecture of Thymic Medulla

MHC class II expression through a hitherto unknown pathway supports T helper cell-dependent immune responses: implications for MHC class II deficiency

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