A strategy to reconstitute immunity without GVHD via adoptive allogeneic Tscm therapy

• Published in: Frontiers in immunology 2024-07, Vol.15, p.1367609
• Main Authors: Guan, Liping, Sun, Yunqin, Si, Yanli, Yan, Qingya, Han, Ziyu, Liu, Youxun, Han, Tao
• Format: Article
• Language: English
• Subjects: adoptive immunotherapy; Adoptive Transfer - methods; alloreactive T cells; Animals; Disease Models, Animal; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; graft-versus-host disease; Immune Reconstitution; Immunotherapy, Adoptive - methods; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; T memory stem cells; T-Lymphocytes - immunology; Transplantation, Homologous
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1367609

Adoption of allogeneic T cells directly supplements the number of T cells and rapidly induces T-cell immunity, which has good efficacy for treating some tumors and immunodeficiency diseases. However, poor adoptive T-cell engraftment and graft-versus-host disease (GVHD) limit the application of these methods. Alloreactive T-cell clones were eliminated from the donor T-cell repertoire, and the remaining T-cell clones were prepared as Tscm for T-cell adoptive treatment to reconstruct recipient T-cell immunity without GVHD. The subjects in this study included three different strains of mice. Lymphocytes from mice (C57BL/6) were used as the donor T-cell repertoire, from which the Tscm allo-reactive T cell clone was depleted (ATD-Tscm). This was confirmed by showing that the Tscm was not responsive to the alloantigen of the recipient (BALB/c). To prepare ATD-Tscm cells, we used recipient lymphocytes as a simulator, and coculture of mouse and recipient lymphocytes was carried out for 7 days. Sorting of non-proliferative cells ensured that the prepared Tscm cells were nonresponsive. The sorted lymphocytes underwent further expansion by treatment with TWS119 and cytokines for an additional 10 days, after which the number of ATD-Tscm cells increased. The prepared Tscm cells were transferred into recipient mice to observe immune reconstitution and GVHD incidence. Our protocol began with the use of 1×10 donor lymphocytes and resulted in 1 ×10 ATD-Tscm cells after 17 days of preparation. The prepared ATD-Tscm cells exhibited a nonresponse upon restimulation of the recipient lymphocytes. Importantly, the prepared ATD-Tscm cells were able to bind long and reconstitute other T-cell subsets , effectively recognizing and answering the "foreign" antigen without causing GVHD after they were transferred into the recipients. Our strategy was succeeded to prepare ATD-Tscm cells from the donor T-cell repertoire. The prepared ATD-Tscm cells were able to reconstitute the immune system and prevent GVHD after transferred to the recipients. This study provides a good reference for generating ATD-Tscm for T-cell adoptive immunotherapy.