MHC Class 1 vs 2: Key Distinctions for Immune Health

The immune system relies on major histocompatibility complex (MHC) molecules to identify and respond to threats. These molecules present antigens to T cells, helping the body distinguish between self and non-self. Two primary classes, MHC class I and MHC class II, serve distinct functions essential for both defending against infections and maintaining immune balance.

Understanding their differences provides insight into how the immune system detects pathogens, activates responses, and sometimes misfires in autoimmune diseases.

Molecular Distinctions

MHC class I and MHC class II molecules differ structurally in ways that influence their function, primarily in polypeptide composition, antigen-binding groove configuration, and reliance on accessory molecules.

Polypeptide Composition

MHC class I molecules consist of a single transmembrane heavy chain (α chain) of approximately 45 kDa, non-covalently associated with β2-microglobulin, a 12 kDa protein. The α1 and α2 domains form the antigen-binding groove. In contrast, MHC class II molecules have two transmembrane chains: an α chain (~34 kDa) and a β chain (~29 kDa), both contributing to the binding groove. Unlike MHC class I, which requires β2-microglobulin for stability, MHC class II does not associate with this molecule.

Binding Groove Configuration

The antigen-binding groove of MHC class I is closed-ended, accommodating peptides typically 8–10 amino acids long. Conserved residues at the groove’s ends anchor the peptide termini, limiting flexibility. MHC class II has an open-ended groove, allowing it to bind peptides of 13–25 amino acids. This structural difference enables MHC class II to present larger antigenic fragments, while MHC class I is restricted to shorter peptides.

Accessory Molecules

MHC class I molecules rely on chaperone proteins, including calnexin, calreticulin, and tapasin, to assist with folding and peptide loading in the endoplasmic reticulum. Tapasin facilitates interaction with the transporter associated with antigen processing (TAP), ensuring high-affinity peptide selection. MHC class II associates with the invariant chain (Ii) during assembly, preventing premature peptide binding. The invariant chain is later degraded in the endosomal pathway, leaving behind CLIP (class II-associated invariant chain peptide), which is replaced by antigenic peptides through HLA-DM.

Antigen Processing Pathways

MHC class I and MHC class II follow distinct intracellular routes for antigen processing, dictated by antigen origin, degradation mechanisms, and compartmentalization.

MHC class I presents peptides from endogenous proteins synthesized within the cytoplasm. Degradation begins with the proteasome, which cleaves proteins into short peptides. In antigen-presenting cells exposed to inflammation, an immunoproteasome enhances the generation of peptides suited for MHC class I binding. Peptides are transported into the endoplasmic reticulum by TAP, where chaperone proteins facilitate loading onto MHC class I molecules before transport to the cell surface.

MHC class II presents peptides from exogenous proteins internalized through endocytosis, phagocytosis, or macropinocytosis. These proteins are degraded in endosomal vesicles by proteases such as cathepsins. Unlike MHC class I, which acquires peptides in the ER, MHC class II is synthesized with an invariant chain occupying its binding groove to prevent premature peptide loading. As MHC class II transits through the endosomal system, the invariant chain is cleaved, leaving CLIP, which is replaced by antigenic peptides through HLA-DM.

Distribution in Cell Types

MHC class I is found on nearly all nucleated cells, ensuring intracellular protein fragments are continuously displayed. This widespread distribution allows for constant immune surveillance, particularly in metabolically active tissues. Even immune-privileged sites, like the brain, exhibit basal MHC class I expression, though neurons maintain lower levels compared to microglia, which engage in antigen presentation under inflammation.

MHC class II is typically restricted to professional antigen-presenting cells (APCs), including dendritic cells, macrophages, and B cells. These cells reside in lymphoid organs, mucosal surfaces, and peripheral tissues, interacting with environmental antigens. Dendritic cells, particularly Langerhans cells in the skin and mucosa, efficiently capture and process extracellular material. Macrophages express MHC class II at varying levels, increasing expression upon exposure to interferon-gamma (IFN-γ). B cells, while primarily involved in antibody production, also use MHC class II to interact with helper T cells in lymphoid organs.

Certain conditions can induce MHC class II expression in non-immune tissues. Endothelial and epithelial cells upregulate MHC class II during prolonged inflammation or infection, contributing to immune activation in autoimmune diseases. Thymic epithelial cells uniquely express both MHC class I and MHC class II, shaping T cell development by selecting self-tolerant lymphocytes.

Role in T-Cell Activation

T-cell activation depends on interactions between T-cell receptors (TCRs) and peptide-MHC complexes, with MHC class I and MHC class II engaging distinct T-cell subsets.

MHC class I presents peptides to CD8+ T cells, responsible for cytotoxic responses. Upon activation, CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs). The affinity of the TCR for the MHC-peptide complex, along with co-stimulatory signals such as CD28 binding to B7 on antigen-presenting cells, determines whether a CD8+ T cell initiates an immune response. CD8, a co-receptor, stabilizes the interaction with MHC class I.

MHC class II presents extracellularly derived peptides to CD4+ T cells, which coordinate immune responses. CD4+ T cells differentiate into subsets like Th1, Th2, Th17, or T follicular helper (Tfh) cells, each directing specific immune pathways. CD4 stabilizes the interaction with MHC class II, ensuring proper antigen recognition. Unlike CD8+ T cells, CD4+ T cells often engage in prolonged interactions with antigen-presenting cells, receiving additional signals that reinforce activation.

Autoimmune and Infectious Context

MHC class I and MHC class II influence susceptibility to autoimmune diseases and immune responses against infections. Variations in MHC gene expression and peptide-binding specificity determine how the immune system distinguishes between self and non-self, sometimes leading to unintended immune activation or immune evasion by pathogens.

In autoimmune diseases, aberrant MHC class II activity is often implicated due to its role in presenting extracellular antigens to CD4+ T cells. Certain alleles, such as HLA-DR4 in rheumatoid arthritis or HLA-DQ8 in type 1 diabetes, increase the likelihood of self-reactive T cells becoming activated. This occurs when self-protein-derived peptides bind with high affinity to MHC class II, triggering helper T-cell responses that sustain chronic inflammation. Molecular mimicry, where foreign antigens resemble self-peptides, can drive T-cell cross-reactivity, as seen in multiple sclerosis, where myelin-derived peptides are misrecognized due to similarities with viral antigens. While MHC class I is less commonly associated with autoimmunity, it plays a role in conditions like ankylosing spondylitis, where HLA-B27 disrupts immune tolerance.

In infections, MHC class I is crucial for antiviral defenses. Viruses like cytomegalovirus (CMV) and Epstein-Barr virus (EBV) evade detection by downregulating TAP transporters or interfering with peptide loading, allowing infected cells to escape CD8+ T cell recognition. MHC class II is essential for coordinating immune responses against extracellular bacteria and parasites. Pathogens such as Mycobacterium tuberculosis manipulate MHC class II antigen processing by inhibiting phagosome maturation, preventing effective antigen presentation to CD4+ T cells. These strategies highlight how pathogens exploit MHC-related mechanisms to evade immune detection, influencing disease progression and treatment strategies.