Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing.

Hershberg, Robert M.; Framson, Paul E.; Cho, Diane H.; Lee, Lawrence Y.; Kovats, Susan; Beitz, Jill; Blum, Janice S.; Nepom, Gerald T.

doi:10.1172/jci119514

Cited by 202 publications

(148 citation statements)

References 49 publications

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“…However, because an alloantigenic T lymphocyte reaction is not equivalent to an Ag-specific study, further Ag-specific in vivo studies are required to prove the involvement of CMFs in direct Ag uptake and presentation in the colon. Nonetheless, the experiments using an HLA-DR-restricted T cell line (9) and CMFs engineered to express the specific HLA-DR allele (HLA-DRB1*0401) demonstrated that processing and presentation of HSA by CMFs induces significant activation of the T cell hybridoma. Taken together, these data indicate that CMFs can present foreign Ags and activate resting CD4 ϩ T cells in an MHC class II-dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

“…The HLA-DR␣ and -DR␤ containing retroviral vectors have been described and were provided by Dr. R. Hershberg (Corixa, Seattle, WA) (9). Briefly, the HLA-DR␣ and -DRB1*0401 cDNA were expressed under the control of the CMV-IE promoter and the cDNA for the dominant selectable marker (hygromycin resistance for the DRA vector and neomycin resistance for the DRB1*0401 vector) was expressed under the control of the viral long terminal repeat.…”

Section: Generation Of Retroviral Infectantsmentioning

confidence: 99%

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Subepithelial Myofibroblasts are Novel Nonprofessional APCs in the Human Colonic Mucosa

Saada¹,

Pinchuk²,

Barrera³

et al. 2006

The Journal of Immunology

110

139

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The human gastrointestinal mucosa is exposed to a diverse normal microflora and dietary Ags and is a common site of entry for pathogens. The mucosal immune system must respond to these diverse signals with either the initiation of immunity or tolerance. APCs are important accessory cells that modulate T cell responses which initiate and maintain adaptive immunity. The ability of APCs to communicate with CD4+ T cells is largely dependent on the expression of class II MHC molecules by the APCs. Using immunohistochemistry, confocal microscopy, and flow cytometry, we demonstrate that α-smooth muscle actin+, CD90+ subepithelial myofibroblasts (stromal cells) constitutively express class II MHC molecules in normal colonic mucosa and that they are distinct from professional APCs such as macrophages and dendritic cells. Primary isolates of human colonic myofibroblasts (CMFs) cultured in vitro were able to stimulate allogeneic CD4+ T cell proliferation. This process was dependent on class II MHC and CD80/86 costimulatory molecule expression by the myofibroblasts. We also demonstrate that CMFs, engineered to express a specific DR4 allele, can process and present human serum albumin to a human serum albumin-specific and DR4 allele-restricted T cell hybridoma. These studies characterize a novel cell phenotype which, due to its strategic location and class II MHC expression, may be involved in capture of Ags that cross the epithelial barrier and present them to lamina propria CD4+ T cells. Thus, human CMFs may be important in regulating local immunity in the colon.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Generation Of Retroviral Infectantsmentioning

confidence: 99%

Subepithelial Myofibroblasts are Novel Nonprofessional APCs in the Human Colonic Mucosa

Saada¹,

Pinchuk²,

Barrera³

et al. 2006

The Journal of Immunology

110

139

View full text Add to dashboard Cite

show abstract

“…[13][14][15][16] Most of these molecules are in part transcriptionally regulated by the transcription factor nuclear factor (NF)-jB. 17 Although bacteria trigger host responses by multiple mechanisms, the cornerstone of innate signalling is mediated by TLRs, a set of 10 well conserved pattern recognition receptors (PRR).…”

Section: Discussionmentioning

confidence: 99%

Innate mechanisms for Bifidobacterium lactis to activate transient pro‐inflammatory host responses in intestinal epithelial cells after the colonization of germ‐free rats

et al. 2005

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“…Samples were analyzed on a FACScan using CellQuest software (BD Bioscience, Mountain View, CA). Background fluorescence was evaluated using irrelevant isotype-matched antibodies (IN-1 and NN4) as described [47,52].…”

Section: Competitive Peptide Binding Assaysmentioning

confidence: 99%

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII [261][262][263][264][265][266][267][268][269][270][271][272][273] , which binds to HLA-DR4 and activates CD4 + T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII 261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope to activate CD4 + T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide is internalized by APC and edited by HLA-DM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class IImediated CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope presentation and regulates CD4 + T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.Key words: CD4 + T cells Á HLA-DM Á HLA-DR Á Peptide presentation Á Type II collagen IntroductionType II collagen (CII) is the major protein component of articular cartilage [1]. It is thought that T and B cell responses to this autoantigen are associated with the development and pathogenesis of rheumatoid arthritis (RA) [2,3]. It is also widely believed that RA is genetically linked to HLA class II molecules, including some HLA-DR4 alleles, and that T cell responses in collagendependent RA are directed towards the immunodominant pathogenic epitope CII [261][262][263][264][265][266][267][268][269][270][271][272][273] [4,5]. Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur. J. Immunol. 2008. 38: 1961-1970 Immunomodulation in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5...

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Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing.

Cited by 202 publications

References 49 publications

Subepithelial Myofibroblasts are Novel Nonprofessional APCs in the Human Colonic Mucosa

Subepithelial Myofibroblasts are Novel Nonprofessional APCs in the Human Colonic Mucosa

Innate mechanisms for Bifidobacterium lactis to activate transient pro‐inflammatory host responses in intestinal epithelial cells after the colonization of germ‐free rats

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

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