MRT-201

T cell-mediated immune response plays a key role in Takayasu arteritis (TAK). Although previous studies have showed the roles of CD4⁺T cell and its subsets in TAK, the change of CD8⁺ T cell subsets remains unclear. This study investigated the role of CD8⁺ T cell subsets in TAK.

The study consisted of 56 TA patients and 51 healthy controls. The percentages of CD8⁺T cells, CD8⁺GranzymeB⁺ T cells, CD8⁺Perforin⁺ T cells, and CD8⁺IFN-γ⁺ T cells in blood samples were analyzed by flow cytometry.

We found that the percentages of CD8⁺GranzymeB⁺ T cells (P = 0.030), CD8⁺Perforin⁺ T cells (P = 0.000), and CD8⁺IFN-γ⁺ T cells (P = 0.002) in CD8⁺T cells were higher in TAK patients compared to control group. After 6 months of treatment, the proportion of CD8⁺T cells in lymphocytes were significantly lower in TAK patients than the baseline assessment (P = 0.033). A lower ratio of CD8⁺GranzymeB⁺ T cells/CD8⁺ T cells were showed in TAK patents after treatment compared with TAK patients before treatments (P = 0.011). The change of CD8⁺GranzymeB⁺ T cells/CD8⁺ T cells ratio was positively correlated with the change of ITAS (r = 0.721, P = 0.002) and ITAS-A (r = 0.637, P = 0.008). Finally, the immunofluorescence staining showed the infiltration of CD8⁺ Granzyme B ⁺ cells in the aortic tissue of TAK patients.

Our results disclose that the CD8⁺ T lymphocytes may play a role in TAK pathogenesis. Targeting CD8⁺GranzymeB⁺ T lymphocytes or Granzyme B inhibitors could be a potential therapeutic approach for the treatment of TAK. Key Points • Our study investigated role the of CD8⁺ T cell subsets in TAK. • We found the percentages of CD8⁺GranzymeB⁺ T cells, CD8⁺Perforin⁺ T cells, and CD8⁺IFN-γ⁺ T cells in CD3⁺CD8⁺T cells were higher in TAK patients. • The proportion of CD8⁺T cells in lymphocytes and the ratio of CD8⁺GranzymeB⁺ T cells/CD8⁺ T cells were significantly lower in TAK patients after treatment.

Staphylococcal enterotoxin C2 (SEC2), a classical representative of superantigens, activates T cells that produce massive cytokines. This characteristic makes SEC2 a promising candidate drug for cancer immunotherapy. Previous study showed that ST-4, a SEC2 mutant, enhanced recognition of mouse T-cell receptor Vβ regions, and activated the increased number of T cells that produced more cytokines. However, the underlying molecular mechanism for stimulation of human peripheral blood mononuclear cells (PBMCs) and antitumor effect on human tumor cells remains unknown. Herein, we showed that ST-4 significantly activated TCR Vβ 12, 13A, 14, 15, 17, and 20 CD4⁺ and CD8⁺ T cells, which produced substantial amounts of granzyme B and perforin. These cytokines exhibited antitumor effect on K562 cells by promoting apoptosis and inducing S-phase cell cycle arrest. Conversely, the granzyme B inhibitor or perforin inhibitor significantly weakened antitumor effect of ST-4, accompanied by a decrease of cleaved proapoptotic BAX and cytochrome c, and an increase of antiapoptotic BCL2. Taken together, these data suggest that granzyme B and perforin produced by ST-4-activated CD4⁺ T cells and CD8⁺ T cells play a pivotal role in inducing K562 cell apoptosis by the mitochondrial apoptotic pathway, and support ST-4 as a potential candidate for cancer immunotherapy.