UniProt functional annotation for P01911



	UniProt functional annotation for P01911

UniProt code: P01911.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA- DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:22327072, PubMed:27591323, PubMed:8642306, PubMed:15265931, PubMed:31495665, PubMed:16148104). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor- resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819). {ECO:0000269|PubMed:15265931, ECO:0000269|PubMed:17182262, ECO:0000269|PubMed:22327072, ECO:0000269|PubMed:23783831, ECO:0000269|PubMed:25413013, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:31495665, ECO:0000269|PubMed:8145819, ECO:0000269|PubMed:8642306}.

Function: Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4- positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:8145819, PubMed:9075930, PubMed:25413013, PubMed:32668259). Presents a self- peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930). {ECO:0000269|PubMed:22327072, ECO:0000269|PubMed:25413013, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:28467828, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:31619516, ECO:0000269|PubMed:32668259, ECO:0000269|PubMed:8145819, ECO:0000269|PubMed:9075930}.

Function: Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self- peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726). {ECO:0000269|PubMed:19830726, ECO:0000269|PubMed:25413013, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:31020640}.

Function: Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M. tuberculosis esxB/culture filtrate antigen CFP- 10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma- associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self- peptides derived from COL2A1 (PubMed:9354468). {ECO:0000269|PubMed:15265931, ECO:0000269|PubMed:24190431, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:8642306, ECO:0000269|PubMed:9354468}.

Function: Allele DRB1*04:02: Displays native or citrullinated self- peptides derived from VIM. {ECO:0000269|PubMed:24190431}.

Function: Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431). {ECO:0000269|PubMed:24190431, ECO:0000269|PubMed:27591323}.

Function: Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies. {ECO:0000269|PubMed:19120973}.

Function: Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load. {ECO:0000269|PubMed:29884618}.

Function: Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus- specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T- helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837). {ECO:0000269|PubMed:22929521, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:30282837, ECO:0000269|PubMed:31308093}.

Function: Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665). {ECO:0000269|PubMed:19830726, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:31495665}.

Function: Allele DRB1*13:01: Presents viral epitopes derived from HHV- 6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection. {ECO:0000269|PubMed:31020640}.

Function: Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self- peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:9782128, PubMed:25413013). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies. {ECO:0000269|PubMed:19120973, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:9782128}.

Function: Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973). {ECO:0000269|PubMed:19120973, ECO:0000269|PubMed:29884618}.

Function: (Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes. {ECO:0000269|PubMed:11864610, ECO:0000269|PubMed:9151859}.

Subunit: Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB1 and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft. As a result, MHCII molecules can not bind peptides present in the ER (PubMed:7479981). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (PubMed:25413013). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment (PubMed:7477400, PubMed:9075930). The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA- DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (PubMed:23260142, PubMed:11070170, PubMed:9075930). Interacts with HLA-DM heterodimer; this interaction is direct (PubMed:25413013). Interacts with TCR (via CDR3) (PubMed:29884618). Interacts (via beta-2 domain) with CD4 coreceptor (via Ig-like V-type domain); this interaction is of exceptionally low affinity yet necessary for optimal recognition of antigenic peptides (PubMed:21900604, PubMed:27114505). {ECO:0000269|PubMed:11070170, ECO:0000269|PubMed:21900604, ECO:0000269|PubMed:23260142, ECO:0000269|PubMed:25413013, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:7477400, ECO:0000269|PubMed:7479981, ECO:0000269|PubMed:9075930, ECO:0000269|PubMed:9354468, ECO:0000269|PubMed:9782128}.

Subunit: (Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD and enterotoxin H/entH. Enterotoxins bind outside the peptide-binding cleft of MHCII: enterotoxin H/entH interacts via the beta-1 domain of MHCII and in a zinc-dependent way, whereas enterotoxin B/entB interacts primarily via the alpha-1 domain. {ECO:0000269|PubMed:11432818, ECO:0000269|PubMed:2210803, ECO:0000269|PubMed:2658055, ECO:0000269|PubMed:8152483}.

Subunit: (Microbial infection) Interacts with Epstein-Barr virus gp42 protein. {ECO:0000269|PubMed:11864610, ECO:0000269|PubMed:9151859}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:19830726, ECO:0000269|PubMed:29884618}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:18305173}; Single-pass type I membrane protein {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Late endosome membrane {ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Autolysosome membrane {ECO:0000269|PubMed:17182262}. Note=The MHC class II complex transits through a number of intracellular compartments in the endocytic pathway until it reaches the cell membrane for antigen presentation (PubMed:18305173). Component of immunological synapses at the interface between T cell and APC (PubMed:29884618). {ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:29884618}.

Tissue specificity: Expressed in professional APCs: monocyte/macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:23783831, PubMed:19830726). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831). {ECO:0000269|PubMed:23783831, ECO:0000269|PubMed:31495665}.

Domain: The beta-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the alpha-1 domain of HLA-DRA. Forms hydrogen bonds with the peptide main chain via conserved amino acid in most HLA-DRB molecules. The polymorphic residues accomodate the side chains of the peptide conferring peptide specificity to distinct HLA-DRB1 alleles (PubMed:8145819, PubMed:28467828, PubMed:9782128, PubMed:9354468). The peptide-bound beta-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domains of TCR (PubMed:19303388). {ECO:0000269|PubMed:19303388, ECO:0000269|PubMed:28467828, ECO:0000269|PubMed:8145819, ECO:0000269|PubMed:9354468, ECO:0000269|PubMed:9782128}.

Domain: The beta-2 Ig-like domain mediates the interaction with CD4 coreceptor. {ECO:0000269|PubMed:27114505, ECO:0000305|PubMed:21900604}.

Ptm: Ubiquitinated by MARCHF1 and MARCHF8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHCII. {ECO:0000305|PubMed:18305173}.

Polymorphism: Highly polymorphic. Polymorphic residues encode for the beta-1 domain of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The sequence shown is that of DRB1*15:01. The sequences of common representative alleles of serologically distinct allele groups as defined in the catalog of common and well-documented HLA alleles, are described as variants of DRB1*15:01 (PubMed:23510415). In the context of hematological malignancy and T cell transplantation, alleles DRB1*03:01 and DRB1*13:01 present minor histocompatibility antigens derived respectively from host MTHFD1 and LY75 proteins, contributing to T cell-mediated graft-versus-leukemia effect and complete remission (PubMed:19706888). {ECO:0000269|PubMed:19706888, ECO:0000269|PubMed:23510415, ECO:0000305|PubMed:23510415}.

Disease: Note=In populations of European descent, allele DRB1*01:03 is associated with increased susceptibility to Crohn disease and colonic ulcerative colitis. Decreased heterozygosity in individuals with colonic ulcerative colitis suggests that it acts as a recessive risk allele. {ECO:0000269|PubMed:25559196}.

Disease: Sarcoidosis 1 (SS1) [MIM:181000]: An idiopathic, systemic, inflammatory disease characterized by the formation of immune granulomas in involved organs. Granulomas predominantly invade the lungs and the lymphatic system, but also skin, liver, spleen, eyes and other organs may be involved. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:02, DRB1*11:01 and DRB1*12:01 are associated with sarcoidosis. Allele DRB1*04:02 is significantly associated with specific sarcodosis phenotypes such as eye, parotid and salivary gland involvement. {ECO:0000269|PubMed:14508706}.

Disease: Multiple sclerosis (MS) [MIM:126200]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. In populations of European descent, allele DRB1*15:01 has the strongest association with multiple sclerosis among all HLA class II alleles. Additional risk is associated with the strongly linked alleles DRB1*03:01 and DQB1*02:01 as well as with allele DRB1*13:03 (PubMed:21833088). It is postulated that bacterial or viral infection triggers the autoimmune MS. Microbial peptides having low affinity crossreactivity to MBP autoantigen, may stimulate autoreactive T cells via molecular mimicry and initiate the autoimmune inflammation (PubMed:19303388). {ECO:0000269|PubMed:19303388, ECO:0000269|PubMed:21833088}.

Disease: Note=Allele DRB1*15:01 is associated with increased susceptibility to Goodpasture syndrome. Can present a self-peptide derived from COL4A3 (GWISLWKGFSF) on TCR (TRAV19 biased) in pathogenic CD4-positive T-helper 1 and T-helper 17 cells, triggering autoimmune inflammation. {ECO:0000269|PubMed:28467828}.

Disease: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:22286218}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:01; DRB1*04:04; DRB1*04:05; DRB1*04:08; DRB1*10:01; DRB1*01:01 and DRB1*01:02 are associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis). Variations at position 40 in the peptide-binding cleft of these alleles explain most of the association to rheumatoid arthritis risk. {ECO:0000269|PubMed:22286218}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA- DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:22327072, PubMed:27591323, PubMed:8642306, PubMed:15265931, PubMed:31495665, PubMed:16148104). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor- resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819). {ECO:0000269\|PubMed:15265931, ECO:0000269\|PubMed:17182262, ECO:0000269\|PubMed:22327072, ECO:0000269\|PubMed:23783831, ECO:0000269\|PubMed:25413013, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:31495665, ECO:0000269\|PubMed:8145819, ECO:0000269\|PubMed:8642306}.



Function:		Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4- positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:8145819, PubMed:9075930, PubMed:25413013, PubMed:32668259). Presents a self- peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930). {ECO:0000269\|PubMed:22327072, ECO:0000269\|PubMed:25413013, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:28467828, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:31619516, ECO:0000269\|PubMed:32668259, ECO:0000269\|PubMed:8145819, ECO:0000269\|PubMed:9075930}.



Function:		Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self- peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726). {ECO:0000269\|PubMed:19830726, ECO:0000269\|PubMed:25413013, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:31020640}.



Function:		Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M. tuberculosis esxB/culture filtrate antigen CFP- 10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma- associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self- peptides derived from COL2A1 (PubMed:9354468). {ECO:0000269\|PubMed:15265931, ECO:0000269\|PubMed:24190431, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:8642306, ECO:0000269\|PubMed:9354468}.



Function:		Allele DRB1*04:02: Displays native or citrullinated self- peptides derived from VIM. {ECO:0000269\|PubMed:24190431}.



Function:		Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431). {ECO:0000269\|PubMed:24190431, ECO:0000269\|PubMed:27591323}.



Function:		Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies. {ECO:0000269\|PubMed:19120973}.



Function:		Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load. {ECO:0000269\|PubMed:29884618}.



Function:		Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus- specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T- helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837). {ECO:0000269\|PubMed:22929521, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:30282837, ECO:0000269\|PubMed:31308093}.



Function:		Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665). {ECO:0000269\|PubMed:19830726, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:31495665}.



Function:		Allele DRB1*13:01: Presents viral epitopes derived from HHV- 6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection. {ECO:0000269\|PubMed:31020640}.



Function:		Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self- peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:9782128, PubMed:25413013). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies. {ECO:0000269\|PubMed:19120973, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:9782128}.



Function:		Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973). {ECO:0000269\|PubMed:19120973, ECO:0000269\|PubMed:29884618}.



Function:		(Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes. {ECO:0000269\|PubMed:11864610, ECO:0000269\|PubMed:9151859}.


Subunit:		Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB1 and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft. As a result, MHCII molecules can not bind peptides present in the ER (PubMed:7479981). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (PubMed:25413013). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment (PubMed:7477400, PubMed:9075930). The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA- DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (PubMed:23260142, PubMed:11070170, PubMed:9075930). Interacts with HLA-DM heterodimer; this interaction is direct (PubMed:25413013). Interacts with TCR (via CDR3) (PubMed:29884618). Interacts (via beta-2 domain) with CD4 coreceptor (via Ig-like V-type domain); this interaction is of exceptionally low affinity yet necessary for optimal recognition of antigenic peptides (PubMed:21900604, PubMed:27114505). {ECO:0000269\|PubMed:11070170, ECO:0000269\|PubMed:21900604, ECO:0000269\|PubMed:23260142, ECO:0000269\|PubMed:25413013, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:7477400, ECO:0000269\|PubMed:7479981, ECO:0000269\|PubMed:9075930, ECO:0000269\|PubMed:9354468, ECO:0000269\|PubMed:9782128}.
Subunit:		(Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD and enterotoxin H/entH. Enterotoxins bind outside the peptide-binding cleft of MHCII: enterotoxin H/entH interacts via the beta-1 domain of MHCII and in a zinc-dependent way, whereas enterotoxin B/entB interacts primarily via the alpha-1 domain. {ECO:0000269\|PubMed:11432818, ECO:0000269\|PubMed:2210803, ECO:0000269\|PubMed:2658055, ECO:0000269\|PubMed:8152483}.
Subunit:		(Microbial infection) Interacts with Epstein-Barr virus gp42 protein. {ECO:0000269\|PubMed:11864610, ECO:0000269\|PubMed:9151859}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:19830726, ECO:0000269\|PubMed:29884618}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269\|PubMed:18305173}; Single-pass type I membrane protein {ECO:0000255}. Lysosome membrane {ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Late endosome membrane {ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Autolysosome membrane {ECO:0000269\|PubMed:17182262}. Note=The MHC class II complex transits through a number of intracellular compartments in the endocytic pathway until it reaches the cell membrane for antigen presentation (PubMed:18305173). Component of immunological synapses at the interface between T cell and APC (PubMed:29884618). {ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:29884618}.
Tissue specificity:		Expressed in professional APCs: monocyte/macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:23783831, PubMed:19830726). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831). {ECO:0000269\|PubMed:23783831, ECO:0000269\|PubMed:31495665}.
Domain:		The beta-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the alpha-1 domain of HLA-DRA. Forms hydrogen bonds with the peptide main chain via conserved amino acid in most HLA-DRB molecules. The polymorphic residues accomodate the side chains of the peptide conferring peptide specificity to distinct HLA-DRB1 alleles (PubMed:8145819, PubMed:28467828, PubMed:9782128, PubMed:9354468). The peptide-bound beta-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domains of TCR (PubMed:19303388). {ECO:0000269\|PubMed:19303388, ECO:0000269\|PubMed:28467828, ECO:0000269\|PubMed:8145819, ECO:0000269\|PubMed:9354468, ECO:0000269\|PubMed:9782128}.
Domain:		The beta-2 Ig-like domain mediates the interaction with CD4 coreceptor. {ECO:0000269\|PubMed:27114505, ECO:0000305\|PubMed:21900604}.
Ptm:		Ubiquitinated by MARCHF1 and MARCHF8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHCII. {ECO:0000305\|PubMed:18305173}.
Polymorphism:		Highly polymorphic. Polymorphic residues encode for the beta-1 domain of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The sequence shown is that of DRB115:01. The sequences of common representative alleles of serologically distinct allele groups as defined in the catalog of common and well-documented HLA alleles, are described as variants of DRB115:01 (PubMed:23510415). In the context of hematological malignancy and T cell transplantation, alleles DRB103:01 and DRB113:01 present minor histocompatibility antigens derived respectively from host MTHFD1 and LY75 proteins, contributing to T cell-mediated graft-versus-leukemia effect and complete remission (PubMed:19706888). {ECO:0000269\|PubMed:19706888, ECO:0000269\|PubMed:23510415, ECO:0000305\|PubMed:23510415}.
Disease:		Note=In populations of European descent, allele DRB1*01:03 is associated with increased susceptibility to Crohn disease and colonic ulcerative colitis. Decreased heterozygosity in individuals with colonic ulcerative colitis suggests that it acts as a recessive risk allele. {ECO:0000269\|PubMed:25559196}.
Disease:		Sarcoidosis 1 (SS1) [MIM:181000]: An idiopathic, systemic, inflammatory disease characterized by the formation of immune granulomas in involved organs. Granulomas predominantly invade the lungs and the lymphatic system, but also skin, liver, spleen, eyes and other organs may be involved. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB104:02, DRB111:01 and DRB112:01 are associated with sarcoidosis. Allele DRB104:02 is significantly associated with specific sarcodosis phenotypes such as eye, parotid and salivary gland involvement. {ECO:0000269\|PubMed:14508706}.
Disease:		Multiple sclerosis (MS) [MIM:126200]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. In populations of European descent, allele DRB115:01 has the strongest association with multiple sclerosis among all HLA class II alleles. Additional risk is associated with the strongly linked alleles DRB103:01 and DQB102:01 as well as with allele DRB113:03 (PubMed:21833088). It is postulated that bacterial or viral infection triggers the autoimmune MS. Microbial peptides having low affinity crossreactivity to MBP autoantigen, may stimulate autoreactive T cells via molecular mimicry and initiate the autoimmune inflammation (PubMed:19303388). {ECO:0000269\|PubMed:19303388, ECO:0000269\|PubMed:21833088}.
Disease:		Note=Allele DRB1*15:01 is associated with increased susceptibility to Goodpasture syndrome. Can present a self-peptide derived from COL4A3 (GWISLWKGFSF) on TCR (TRAV19 biased) in pathogenic CD4-positive T-helper 1 and T-helper 17 cells, triggering autoimmune inflammation. {ECO:0000269\|PubMed:28467828}.
Disease:		Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269\|PubMed:22286218}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB104:01; DRB104:04; DRB104:05; DRB104:08; DRB110:01; DRB101:01 and DRB1*01:02 are associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis). Variations at position 40 in the peptide-binding cleft of these alleles explain most of the association to rheumatoid arthritis risk. {ECO:0000269\|PubMed:22286218}.