REVIEW article
Front. Genet.
Sec. Immunogenetics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1661511
Emerging Roles of Natural Killer Cell Ligands—HLA-E, HLA-F, HLA-G, MICA, and MICB—in Influencing In Vitro Fertilization Outcomes
Provisionally accepted
- 1Department of Molecular Immunology & Microbiology, Indian Council of Medical Research, National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), India., Parel, Mumbai, India
- 2University of California, San Francisco, San Francisco, United States
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Infertility affects approximately one in six individuals globally and represents a complex public health concern influenced by a range of biological, environmental, and socioeconomic factors. In vitro fertilization (IVF) has emerged as a pivotal assisted reproductive technology, yet its success is often hindered by recurrent implantation failure (RIF) and pregnancy complications such as preeclampsia. Recent research highlights the critical role of the immune system particularly nonclassical Human Leukocyte Antigen (HLA) class I molecules (HLA-G, HLA-E, HLA-F) and MHC class I chain-related proteins (MICA/B) in modulating maternal-fetal tolerance and determining IVF outcomes. This review synthesizes emerging evidence on the structure, expression, receptor interactions, and polymorphisms of these molecules, emphasizing their roles in embryo implantation, immune modulation, and pregnancy maintenance. Soluble HLA-G (sHLA-G) has shown promise as a biomarker for embryo viability, while variations in KIR–HLA interactions and polymorphisms in non-classical HLA genes have been linked to RIF and adverse reproductive outcomes. Despite promising findings, routine clinical testing of these markers remains limited due to methodological inconsistencies, lack of large-scale validation, and the multifactorial nature of implantation. Future research priorities include functional genomics, standardized diagnostic assays, AI-driven predictive tools, and translational trials of immunomodulatory therapies. Understanding the immunogenetic landscape offers new avenues for personalized reproductive care and improved IVF success rates.
Keywords: Infertility, In-vitro fertilization (IVF), Non-Classical Human Leukocyte Antigen (HLA), Killercell immunoglobulin-like receptors (KIRs), IVF treatment
Received: 07 Jul 2025; Accepted: 21 Oct 2025.
Copyright: © 2025 Itta and Rajalingam. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Dr Krishna Chaaithanya Itta, ittak@nirrch.res.in
Raja Rajalingam, rajalingam.raja@ucsf.edu
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