Work

MICA Allelic Variation Modulates Secretion and Protein Flexibility, Impacting on NKG2D‐Mediated Immune Responses and Antibody Detection

Year: 2026

Type: article

Abstract: T-cells to eliminate transformed cells. However, release of its ligands promotes immune evasion. Although new therapeutic strategies aim to block NKG2D-ligand shedding, the impact of allelic polymorphism on secretion mechanisms, either as soluble proteins or within extracellular vesicles (EVs), remains insufficiently explored. The glycosyl-phosphatidyl-inositol (GPI)-anchored MICA (MHC class I chain-related gene A) *008 allele is preferentially incorporated into EVs, but little is known about the EV release of other alleles. Here, we compared five MICA alleles and found that non-GPI-MICA can also be incorporated into EVs through a palmitoylation-dependent process, although with much lower efficiency compared with GPI-anchored alleles, such as MICA*008. EVs containing MICA decreased NKG2D detection and impaired NK cell function, whereas soluble MICA had negligible effects. The strength of these effects was related to MICA allele identity. In addition to affinity (ruled by dimorphism at position 129), predictions of differences in MICA structural dynamics and NKG2D binding energetics coincided with the differential capacity of alleles to modulate NKG2D and to bind certain anti-MICA antibodies. Given the clinical potential of MICA as a biomarker and therapeutic target, defining the biology and immune impact of allelic variants is essential to optimize strategies aimed at restoring NKG2D-dependent antitumor immunity.

Source: European Journal of Immunology

DOI: 10.1002/eji.70304

Authors: Silvia López‐Borrego, Karen Toledo‐Stuardo, Douglas J. Matthies, Marta González‐Matesanz, María Carmen Molina, Mar Valés‐Gómez

Institutions: Consejo Superior de Investigaciones Científicas, Centro Nacional de Biotecnología, University of Chile

Language: English

Topic: Immune Cell Function and Interaction

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,550