Human Leukocyte Antigens

Background

HLA is located on chromosome 6 in the Major Histocompatibility Complex (MHC).

Figure 1

Classical HLA

HLA Class I

HLA class I molecules are expressed by healthy nucleated cells.

Figure 2

This means that the only healthy nucleated cells that don’t express HLA class I are reticulocytes and erythroctes.

Peptide binding groove ~34 residues (amino acids)

Total amino acids residues ~340

B2 microglobulin 99 amino acid residues

HLA Class II

HLA class II molecules are expressed by professional antigen-presenting cells (APC)–dendritic cells, macrophages, and B cells.

Nomenclature

Non-classical HLA

HLA-E

Natural Killer Cell Interactions

Bw4-motif and KIR3DL1

KIR3DL1 (inhibitory receptor) binds to HLA-A and -B molecules that carry the Bw4-motif, defined by amino acid residues 77-83 in the external-facing α1-helix region. Only select HLA-A molecules have the Bw4-motif. HLA-B molecules carry either the Bw4-motif or Bw6-motif (does not bind KIR3DL1). HLA-C do not carry the Bw4 or Bw6-motifs.

Importantly, there are two Bw4-allotypes defined the amino acid at position 80, either an isoleucine (Bw4-80I) or threonine (Bw4-80T). Bw4-80I is a high affinity for KIR3DL1 whereas Bw4-80T is lower affinity. The higher affinity of Bw4-80I leads to more strongly educated and reactive NK cell populations compared to the lower affinity Bw4-80T. The Bw6-motif does not bind to KIR3DL1.

Bw4-motif spans residues 77, 80-83 (on the alpha 1 helix)

The Bw4 motif is characterized by residues 77-83 (N, L, R, I/T, A, L, R) in the external-facing α1-helix. The Bw6 motif is characterized by residues 77-83 (S, L, R, N, L, R, G) in the external-facing α1-helix.

Figure 3

Functional Divergence

Heterozygosity of HLA class I genes is associated with better outcomes after HIV infection. This is thought to be due to a greater repertoire of HIV peptides presented and cytotoxic T cell response. However, looking at HLA class I allotype alone does not take into account differences in actual peptide repertoire.viard2024? developed a metric to measure this difference, termed “functional divergence.” Functional divergence predicts the peptide repertoire as a continuum. They showed that greater functional divergence was associated with better HIV outcomes. Functional divergence may be relevant to other diseases where HLA heterozygosity confers advantage, such as infection, vaccination, and immunotherapy.

You can download functional divergence estimates for pairwise combinations of HLA-A, HLA-B, and HLA-C alleles from their article’s Supplementary Materials. The functional divergence measure ranges from 0 (i.e., smallest functional divergence) to 1 (i.e., greatest functional divergence).