MHC Class II (HLA-DR/DQ/DP)
MHC class II (human HLA class II) is the cell-surface display platform that links innate pathogen sensing to adaptive CD4+ T cell priming. Three classical isotypes — HLA-DR, HLA-DQ, and HLA-DP — each encoded by distinct α/β gene pairs in the highly polymorphic HLA locus on chromosome 6p21.3 — display peptide fragments (13–25 aa) derived from exogenous (endocytosed) proteins to CD4+ T helper cells. The TCR–pMHC-II interaction is mandatory for naive CD4+ T cell activation, clonal expansion, and differentiation into Th1, Th2, Th17, or Treg effector subsets. Without MHC-II function, virtually all T-dependent humoral and cellular adaptive immune responses fail — explaining the severe combined immunodeficiency (SCID-like) phenotype of MHC class II deficiency (bare lymphocyte syndrome type II).
Structure
MHC-II is a non-covalent αβ heterodimer: an α-chain (~33 kDa) and β-chain (~28 kDa), both type I transmembrane glycoproteins with two extracellular Ig-like domains each, a transmembrane helix, and a short cytoplasmic tail. The peptide-binding groove is formed jointly by the α1 and β1 distal domains.
| Feature | α-chain | β-chain |
|---|---|---|
| Distal domain | α1 (forms left wall of groove) | β1 (forms right wall of groove; most polymorphic) |
| Proximal domain | α2 (Ig-like; relatively invariant) | β2 (Ig-like; contacts CD4 co-receptor) |
| Polymorphism | Limited (<100 alleles for HLA-DRA) | Extreme (HLA-DRB1 >2,000 alleles; defines peptide repertoire) |
Peptide-binding groove: Unlike MHC class I (closed ends, 8–10 aa peptides), the MHC-II groove is open at both ends, accommodating peptides of 13–25 aa. A central nonameric core (P1–P9 positions) makes the key anchoring contacts with groove pockets; flanking residues protrude. Allele-specific anchor pockets in the β1 domain determine which peptide sequences bind stably — explaining why particular HLA alleles predispose to autoimmune diseases or confer resistance to certain infections.
Key HLA-disease associations
| HLA allele | Associated disease | Relative risk | Proposed mechanism |
|---|---|---|---|
| HLA-DQ2 (DQA1*05/DQB1*02) + DQ8 | Coeliac disease | ~30–50× (DQ2); ~6× (DQ8) | DQ2/DQ8 groove preferentially binds deamidated gliadin peptides (tissue transglutaminase modification) → CD4+ T cell activation in lamina propria |
| HLA-DRB1*04:01 (DR4) | Rheumatoid arthritis | ~3–5× | "Shared epitope" (QKRAA/QRRAA sequence in β1 groove positions 70–74) → citrullinated peptide presentation → anti-CCP antibody production |
| HLA-DRB1*03:01 (DR3) | Type 1 diabetes, Graves', SLE, Myasthenia gravis | 2–5× | Presentation of β-cell autoantigens (GAD65, IA-2) to autoreactive CD4+ T cells → B cell help → autoantibody production |
| HLA-DQA1*03:01/DQB1*03:02 | Type 1 diabetes (highest risk) | ~12× (DQ8+DR4) | DQ8 presents insulin peptide InsB9-23 with high affinity to diabetogenic T cells |
| HLA-DRB1*15:01 (DR2) | Multiple sclerosis (protective: DRB1*14) | ~3× | Presentation of myelin basic protein (MBP) and MOG peptides to CD4+ T cells in CNS |
Mechanism — Antigen Processing and CD4 T Cell Activation
EXOGENOUS PROTEIN ANTIGEN (pathogen, vaccine, food protein)
│
▼ Phagocytosis / receptor-mediated endocytosis by APC
(FcR, complement receptors, C-type lectins, macropinocytosis)
│
▼ Phagosome acidification → fusion with lysosome
Cathepsins (B, D, L, S) + Asparaginyl endopeptidase
→ protein → ~15-25 aa peptides
NEWLY SYNTHESISED MHC-II:
ER → Invariant chain (Ii/CD74) associates with αβ dimer
│ Ii blocks groove (prevents self-peptide loading in ER)
│ Ii dileucine motif → targets MHC-II–Ii to MIIC endosomes
▼
MIIC (MHC-II-containing compartment, late endosome):
Ii degraded by cathepsins → leaves CLIP fragment in groove
HLA-DM (non-classical MHC-II) → peptide editor:
CLIP + low-stability peptides exchanged for
HIGH-STABILITY antigen-derived peptides
→ Stable pMHC-II complexes formed
▼
CELL SURFACE: pMHC-II displayed on APC plasma membrane
│
▼ CD4+ T CELL ENCOUNTER:
TCR contacts both MHC-II helices (α1/β1) AND peptide (dual recognition)
CD4 co-receptor contacts β2 domain → recruits Lck kinase
Signal 1: TCR/CD3 complex → CD3ζ ITAM → ZAP-70 → PLCγ → Ca²⁺/NFAT
Signal 2: CD80/86 (APC) – CD28 (T cell) co-stimulation → PI3K → Akt → NFκB
Signal 3: Cytokines from APC (IL-12→Th1; IL-4→Th2; TGF-β+IL-6→Th17; TGF-β→Treg)
→ Naive CD4+ T cell ACTIVATED → clonal expansion → effector differentiation
CIITA — Master regulator of MHC-II expression
CIITA (class II transactivator, MHC2TA gene) is the master transcriptional regulator of MHC-II and all accessory genes (Ii, HLA-DM, HLA-DO). CIITA does not bind DNA directly; it associates with RFX5/RFXANK/RFXAP complex and NF-Y bound to the conserved X–X2–Y promoter sequences of all MHC-II genes. CIITA is constitutively expressed in professional APCs and inducible by IFN-γ (via STAT1–IRF1 axis) in almost all cell types. Biallelic CIITA mutations cause bare lymphocyte syndrome type II — complete MHC-II deficiency with SCID-like combined immunodeficiency.
Viral immune evasion of MHC-II: Multiple pathogens downregulate MHC-II to evade CD4+ T cell surveillance: HSV-1/2 ICP47 blocks TAP, indirectly affecting MHC-II loaded with viral-derived cytoplasmic peptides; HCMV US2/US3 degrade MHC class I (less impact on MHC-II); Mycobacterium tuberculosis arrests phagosome maturation, preventing lysosomal antigen processing; SARS-CoV-2 ORF7a and ORF9b downregulate MHC-II surface expression on infected monocytes, impairing adaptive priming.
MHC-I vs. MHC-II — Key Distinctions
| Feature | MHC Class I | MHC Class II |
|---|---|---|
| Structure | α chain + β2-microglobulin (non-MHC) | α + β chains (both MHC-encoded) |
| Expression | All nucleated cells | Professional APCs; inducible (IFN-γ) on others |
| Antigen source | Intracellular (proteasomal → TAP → ER) | Extracellular (endocytosed → lysosomal) |
| Peptide length | 8–10 aa (closed groove) | 13–25 aa (open groove) |
| T cell target | CD8+ cytotoxic T cells (kill infected cells) | CD4+ helper T cells (orchestrate all adaptive responses) |
| Co-receptor | CD8 (binds α3 domain) | CD4 (binds β2 domain) |
| Master regulator | Transcription driven by IRF1, NF-κB; β2m constitutive | CIITA (constitutive in APCs; IFN-γ-induced elsewhere) |
Pathology
| Condition | MHC-II mechanism | Clinical features |
|---|---|---|
| Bare lymphocyte syndrome type II | CIITA or RFX5/RFXANK/RFXAP mutations → complete MHC-II deficiency → no CD4+ T cell priming | Severe combined immunodeficiency (SCID-like), recurrent bacterial/viral/fungal/parasitic infections from infancy; low CD4+ T cell counts; normal CD8; B cells present but non-functional; fatal without HSCT |
| Coeliac disease | HLA-DQ2/DQ8 presents deamidated gliadin peptides to CD4+ Th1 cells in lamina propria → IEL cytotoxicity + anti-tTG IgA autoantibodies → villous atrophy | Malabsorption, diarrhoea, iron-deficiency anaemia, osteoporosis, dermatitis herpetiformis; gluten-free diet is curative; anti-tTG IgA + HLA-DQ2/DQ8 diagnostic |
| Rheumatoid arthritis | HLA-DRB1 shared epitope presents citrullinated joint peptides (citrullinated vimentin, fibrinogen, α-enolase) → autoreactive CD4+ Th1/Th17 → synovial inflammation + B cell help → ACPA/anti-CCP | Symmetrical inflammatory polyarthritis, erosive joint destruction; anti-CCP highly specific; treat with MTX, biologic DMARDs (anti-TNF, IL-6 blockade, abatacept) |
| Type 1 diabetes | HLA-DQ8 (DQA1*03:01/DQB1*03:02) presents insulin B-chain peptides and GAD65 peptides to diabetogenic CD4+ T cells → Th1 → cytokine damage + CD8+ T cell killing of β cells | Autoimmune destruction of β cells; positive GAD65/IA-2/ZnT8/insulin autoantibodies precede clinical onset by years; Stage 1-3 staging by autoantibody number and dysglycaemia; teplizumab (anti-CD3) delays Stage 3 onset by ~3 years |
| Transplant rejection | Donor MHC-II mismatch → recipient CD4+ T cells directly recognise allogeneic pMHC-II (direct allorecognition) or indirectly recognise processed donor peptides on self MHC-II (indirect) | Acute cellular rejection (days–weeks), chronic rejection (months–years); HLA matching reduces acute rejection; calcineurin inhibitors (tacrolimus, cyclosporine) + mycophenolate + steroids prevent rejection |
Connections
References
- Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015;15(4):203-16. doi:10.1038/nri3818
- Zinkernagel RM, Doherty PC. The discovery of MHC restriction. Immunol Today. 1997;18(1):14-7. doi:10.1016/S0167-5699(97)80008-4
- Robinson J, et al. IPD-IMGT/HLA Database. Nucleic Acids Res. 2020;48(D1):D948-D955. doi:10.1093/nar/gkz950
- Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 9th ed. Elsevier; 2018.
- Matzaraki V, et al. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol. 2017;18(1):76. doi:10.1186/s13059-017-1207-1