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Reduction in Immunogenicity May Boost ESC-based Therapies

Review of “Targeted Disruption of the β2-Microglobulin Gene Minimizes the Immunogenicity of Human Embryonic Stem Cells” from Stem Cells Translational Medicine by Stuart P. Atkinson.

One of the main stumbling blocks for the widespread clinical application of human embryonic stem cell (hESC)-derived cells and tissues is the rejection of these cells by the body’s own immune system, or histoincompatibility [1, 2]. In an attempt to circumnavigate this problem, researchers from the laboratory of Rick A. Wetsel and Dachun Wang (University of Texas Medical School at Houston, USA) have assessed whether the disruption of the cell surface-expressed human leukocyte antigens (HLAs), the major mediators of immune rejection, in hESCs could lead to the generation of universally accepted transplantable cells [3].

Most cell types express HLA-I genes (HLA-A, HLA-B, and HLA-C) and there they function to present “non-self” antigen-processed peptides to cytolytic CD8+ T cells to mediate immune rejection. The HLA-1 proteins are covalently associated with B2-microglobulin (B2M), and any disruption to B2M would stop any antigen presentation via HLA-I proteins. To generate a B2M-null hESC line and assess effects on immunogenicity, the group disrupted both B2M alleles by replacing some exonic sequences with antibiotic resistance cassettes via homologous recombination.

Wild-type hESCs expressed B2M and this expression increased significantly following differentiation and IFN- treatment (known to induce B2M expression and promote immune rejection [4]). However, following homologous recombination and B2M knockout (KO), the authors observed minimal B2M expression and HLA-I cell surface expression under any condition. This knockout did not affect self-renewal, karyotypic stability, or the differentiation propensity, but did endow hESCs and their derivatives with resistance to CD8+ T cell cytolytic activity and infiltration. The associated figure demonstrates a lack of CD8+ T cell infiltration into Matrigel-KO hESC implants injected subcutaneously into immunocompetent mice as compared to Matrigel-wild-type hESC implants. The lack of HLA-1 did, however, mediate an enhanced sensitivity to Natural killer (NK) cell-mediated cytotoxicity, as HLA-I molecules normally mediate NK cell inhibition.

This enhanced sensitivity mediated a reduction in tumor size after the authors injected KO-hESCs into the muscle of immunodeficient NOD-SCID mice as compared to wild-type hESC injection, although NK cell inhibition led to a normalization of tumor size. When the authors repeated this experiment using immunocompetent mice under NK cell inhibition, teratomas formed only from the KO hESCs and these tumors contained cell types derived from all three germ layers.

This study suggests that the reduction in immunogenicity following B2M KO may represent an exciting means to generate a “universal donor” hESC line for routine clinical use. Therefore, the expense and difficulty in generating a range of hESCs to fit all HLA subtypes and/or producing and correcting (if required) patient-specific induced pluripotent stem cells (iPSCs) may be sidestepped. This is, however, contingent on the reduction or avoidance of NK cell cytotoxicity, a task which surely sits atop of the “To Do” list for the study’s authors.


  1. Grinnemo KH, Kumagai-Braesch M, Mansson-Broberg A, et al. Human embryonic stem cells are immunogenic in allogeneic and xenogeneic settings. Reprod Biomed Online 2006;13:712-724.
  2. Grinnemo KH, Genead R, Kumagai-Braesch M, et al. Costimulation blockade induces tolerance to HESC transplanted to the testis and induces regulatory T-cells to HESC transplanted into the heart. Stem Cells 2008;26:1850-1857.
  3. Wang D, Quan Y, Yan Q, et al. Targeted Disruption of the beta2-Microglobulin Gene Minimizes the Immunogenicity of Human Embryonic Stem Cells. Stem Cells Transl Med 2015;4:1234-1245.
  4. Drukker M, Katz G, Urbach A, et al. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A 2002;99:9864-9869.

Rick A. Wetsel and Dachun Wang