The New Kid on the Block: HLA-C, a Key Regulator of Natural Killer Cells in Viral Immunity

Abstract

The human leukocyte antigen system (HLA) is a cluster of highly polymorphic genes essential for the proper function of the immune system, and it has been associated with a wide range of diseases. HLA class I molecules present intracellular host- and pathogen-derived peptides to effector cells of the immune system, inducing immune tolerance in healthy conditions or triggering effective immune responses in pathological situations. HLA-C is the most recently evolved HLA class I molecule, only present in humans and great apes. Differentiating from its older siblings, HLA-A and HLA-B, HLA-C exhibits distinctive features in its expression and interaction partners. HLA-C serves as a natural ligand for multiple members of the killer-cell immunoglobulin-like receptor (KIR) family, which are predominately expressed by natural killer (NK) cells. NK cells are crucial for the early control of viral infections and accumulating evidence indicates that interactions between HLA-C and its respective KIR receptors determine the outcome and progression of viral infections. In this review, we focus on the unique role of HLA-C in regulating NK cell functions and its consequences in the setting of viral infections.

Updated immunomodulatory roles of gut flora and microRNAs in inflammatory bowel diseases

“…Human leukocyte antigen (HLA) class I genes are the most polymorphic loci in human genome, resulting in HLA-I proteins capable of binding and presenting multiple antigenic peptides to cytotoxic T lymphocytes. This study further found that the subjects with HLA-C alleles regulated by miR-148a exhibited better HIV control but increased risk of CD [ 134 ]. Gut microbiota can protect intestinal integrity and alleviate intestinal inflammation by negatively regulating miR-10a expression in DCs and interacting with TLR signaling pathways [ 116 ].…”

Immunogenomics of Killer Cell Immunoglobulin-Like Receptor (KIR) and HLA Class I: Coevolution and Consequences for Human Health

“…91 Thus, although there are some recognized associations with pathogen clearance, 92 it is with course or severity of chronic infection that specific KIR and HLA allotype pairs have the greatest recognized impact. 30,[93][94][95] The now-classic example is human immunodeficiency virus-1 (HIV-1), in which specific combinations of KIR3DL1/S1 and HLA class I allotypes can reduce viral load or prolong the time to development of acquired immunodeficiency syndrome (AIDS). [96][97][98][99] Among other viral infections differentially controlled by KIR and HLA class I diversity, herpes viruses are the most prominent.…”

The novel HLA‐C allele, C*03:538 was identified by next‐generation sequencing

“…HLA‐C molecule is a polymorphic membrane‐bound protein, which plays an important role in protection against some cancer and viruses 1 . HLA‐C molecule also serves as a ligand for some of the killer‐cell immunoglobulin‐like receptor (KIR) family, and interactions between HLA‐C and its respective KIR receptors can regulate the natural killer cells activity 2 . Currently, over 7393 HLA‐C alleles were identified, which encode for 4,095 HLA‐C proteins 3 .…”

“…1 HLA-C molecule also serves as a ligand for some of the killer-cell immunoglobulin-like receptor (KIR) family, and interactions between HLA-C and its respective KIR receptors can regulate the natural killer cells activity. 2 Currently, over 7393 HLA-C alleles were identified, which encode for 4,095 HLA-C proteins. 3 Here, we describe the novel HLA-C allele, officially named as HLA-C*03:538, that has been found in a Chinese individual.…”