H2-Aa, encoding an MHC class II α chain, is crucial for the synthesis of major histocompatibility complex class II (MHC II) molecules. MHC II plays an essential role in antigen presentation and CD4+ T-cell development, thus being vital for immune regulation [1,2,3]. It is involved in the adaptive immune response pathway where professional antigen-presenting cells interact with naïve CD4+ T cells via the T-cell receptor complex [4,5]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying H2-Aa's function.

In a KO mouse model, H2-Aa deficiency led to a quantitative increase in type 2 conventional dendritic cells (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition [2]. In another case, a spontaneous H2-Aa point mutation in mice led to false pre-mRNA splicing, deletion of eight bases in the mRNA, and protein frameshift. This mutation impaired MHC II synthesis, reduced CD4+ T-cell population, and provided a new paradigm to explain type II bare lymphocyte syndrome (BLS) in mice [1]. Additionally, in a conditional knockout mouse model developed to study cell-specific and time-dependent adaptive immune responses in peripheral nerves, microvascular endothelial cell MHC class II expression (dependent on H2-Aa) was found to be necessary for peripheral nerve-specific autoimmunity [4,5].

In conclusion, H2-Aa is essential for MHC II synthesis, which is crucial for antigen presentation and T-cell development in the immune system. KO and CKO mouse models have revealed its role in various disease conditions such as melanoma and autoimmune polyneuropathy, providing insights into potential immunotherapeutic approaches and understanding the mechanisms of autoimmunity [1,2,4,5].