Human leukocyte antigen class I and class II molecules (HLA class I and II)

Human leukocyte antigen (HLA) class I and class II molecules are cell-surface glycoproteins encoded by the Major Histocompatibility Complex (MHC) that are essential for the adaptive immune response (StatPearls, 2023). HLA class I molecules (HLA-A, -B, -C) are expressed on all nucleated cells and present intracellularly derived peptides to CD8+ T cells, whereas HLA class II molecules (HLA-DR, -DP, -DQ) are primarily expressed on professional antigen-presenting cells (APCs) to present extracellularly derived peptides to CD4+ T cells (UniProt, 2024). These molecules are pivotal in the recognition of foreign pathogens and the elimination of mutated cancer cells, but they also serve as the primary barriers to successful organ transplantation due to their high polymorphism (NIH, 2023). In many cancers, HLA expression is downregulated to facilitate immune evasion, while in autoimmune diseases, specific HLA alleles are strongly associated with the inappropriate presentation of self-antigens (PubMed, 2022). Therapeutic interventions include immunosuppressants like Cyclosporine that block HLA-mediated signaling, and novel TCR-engineered T-cell therapies like Afamitresgene autoleucel designed to recognize specific HLA-peptide combinations (Nature Reviews Drug Discovery, 2021). Additionally, monoclonal antibodies targeting HLA-DR or HLA-G are being explored to modulate immune responses in oncology and inflammatory conditions.

Other names

Major Histocompatibility ComplexMHC class I and IIHLA antigensHuman Leukocyte Antigen SystemMHC

Drugs targeting or involving HLA molecules primarily work by modulating the immunological synapse. This includes inhibiting the downstream signaling of the HLA-TCR complex (e.g., calcineurin inhibitors), blocking co-stimulatory signals required for HLA-mediated T-cell activation (e.g., CTLA-4 Ig), or utilizing engineered T-cell receptors (TCRs) and bispecific molecules to specifically recognize and bind peptide-HLA complexes on the surface of target cells (StatPearls, 2023; Nature Reviews Immunology, 2021).