Human MutS Homologue 2 (hMSH2)

Short Introduction of hMSH2

hMSH2 is a critical element of the highly conserved DNA mismatch repair system, normally located in the nucleus and dimerized with human MutS homologue 3 (hMSH3) or human MutS homologue 6 (hMSH6) to form complexes essential for the maintenance of genome integrity. Inherited and acquired defects in hMSH2 are closely related to the pathogenesis of hereditary nonpolyposis colon cancer as well as various sporadic cancers.

Fig.1 Three classes of receptors regulating human γδ T-cell activation. (Kabelitz, 2017)

hMSH2 and γδ T Cells

With a CDR3δ peptide-based affinity screening system, hMSH2 as a putative tumor-associated protein-ligand for human TCR γδ was identified. hMSH2 may have a role in γδ T cell-mediated immune responses.

• Ectopic Expression of HMSH2 on Epithelial Tumor Cell Lines

Cell surface expression is a prerequisite for hMSH2 as a ligand for γδ T cells. Scientists examined the surface expression of hMSH2 on seven human epithelial tumor cell lines, including HeLa, SKOV3, HO8910, ES-2, 803, HR8348, and NCI-H520. HK-2, fibroblasts (derived from the normal tissues of an ovarian cancer patient), and γδ T cells were used as normal cell controls. Flow cytometric analysis with specific anti-hMSH2 Ab (H-300) revealed that 10-70% of the cell population among each of the tested tumor lines expressed hMSH2, whereas normal control cells rarely expressed hMSH2 on their surface, suggesting broadly ectopic surface expression of hMSH2 during carcinogenesis, which raises the possibility as a ligand for γδ T cells.

Fig.2 Ectopically expressed hMSH2 on the human epithelial tumor cell surface. (Dai, 2012)

• hMSH2 Enhanced γδ T Cell-Mediated Tumor Cytolysis In Vitro

Cell lines expressing significant surface hMSH2 were chosen as targets for specific antibody blockade and target gene knockdown with small interfering RNA (siRNAs) in cytolysis assays. γδ T cells were stimulated and expanded with immobilized anti-pan-TCR monoclonal antibodies (mAb) as effectors. The expanded γδ T cells were mainly composed of V2γδ T subset (80-95%) and expressed NKG2D at day 14. Anti-MSH2 Ab (N-20) significantly blocked γδ T cell-mediated cytolysis of HeLa and 803 cells.

Decreased surface expression of hMSH2 on siRNA-treated HeLa and 803 cells was measured by flow cytometry and confocal microscopy. The decreased hMSH2 expression with siRNA I or II interference resulted in significantly reduced cytolysis of HeLa and 803 cells by γδ T cells. The above results from N-20 Ab blocking or siRNA interference suggest that ectopically expressed hMSH2 mediates the recognition of carcinoma cells by human γδ T cells and contributes to γδ T cell-mediated tumor cytolysis.

Cell surface-expressed hMSH2 is a ligand for both Vδ2 TCR and NKG2D receptors and engages in anti-tumor and anti-virus immunity by enhancing the γδ T cell-mediated cytolysis. Creative Biolabs provides our worldwide customers with high-quality services about γδ T cell, to better and deeper understand γδ T cell and its ligand in adaptive immunity. If you have any questions, please contact us.

References

1. Kabelitz, D.; et al. Immunosurveillance by human γδ T lymphocytes: the emerging role of butyrophilins. F1000research. 2017, 6: 782.
2. Dai, Yumei.; et al. Ectopically expressed human tumor biomarker MutS homolog 2 is a novel endogenous ligand that is recognized by human γδ T cells to induce innate anti-tumorous immunity. The Journal of biological chemistry. 2012, 287(20).