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Dendritic Cells Are Critical for the Activation and Expansion of Vδ2⁺ T Cells After Allogeneic Hematopoietic Transplantation.

ABSTRACT: γδ T cells perform antitumor and antiviral effector functions and are involved in both innate and adaptive immunity. Vδ2⁺ T cells represent the predominant γδ T subset in the peripheral blood of healthy subjects. Vδ2⁺ T cells can be selectively activated and expanded by phosphoantigens (pAgs). Dendritic cells (DCs), as potent antigen-presenting cells, are capable of mediating pAgs-triggered Vδ2⁺ T cells expansion. However, the association between DCs and Vδ2⁺ T cell recovery in the context of hematopoietic stem cell transplantation (HSCT) remains unclear. We previously demonstrated that the recovery of Vδ2⁺ T cells was hampered and inversely correlated with Epstein-Barr virus (EBV) reactivation in patients undergoing haploidentical HSCT (haploHSCT). Whether Vδ2⁺ T cells from haploHSCT recipients can be expanded by stimulation with aminobisphosphonates or pAg-presenting DCs is of particular interest. Herein, we showed that Vδ2⁺ T cells recovered after haploHSCT failed to expand after ex-vivo stimulation with pamidronate. In addition, we found that the recovery of DC subsets was significantly decreased, and the concentration of myeloid DCs (mDCs) correlated significantly with Vδ2⁺ T cell recovery in the setting of allogeneic HSCT. Furthermore, coculture of peripheral lymphocytes from recipients with monocyte-derived and pamidronate-pretreated autologous or allogeneic DCs induced the successful expansion of Vδ2⁺ T cells. Of note, allogeneic DCs from third-party donors stimulated a significantly higher efficiency of Vδ2⁺ T cell expansion than autologous DCs. More importantly, the memory features were well-retained and the cytotoxic cytokines-production capacity was significantly enhanced in the expanded Vδ2⁺ T cells. Taken together, these results suggest that the frequency and function of DCs are critical for the recovery of Vδ2⁺ T cells after allogeneic HSCT. The fact that vigorous expansions of Vδ2⁺ T cells were induced by phosphoantigen-pretreated DCs, especially by allogeneic third-party DCs, provides additional options for the development of individualized immunotherapy strategies that utilize the anti-viral and anti-leukemic effects of γδ T cells in the context of hematopoietic transplantation.

SUBMITTER: Wang X

PROVIDER: S-EPMC6221956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Invariant natural killer T (iNKT) cells are innate-like T lymphocytes cells that recognize glycolipid antigens associated with CD1d, non-classical antigen presenting proteins. They can drive either pro-inflammatory (Th-1) or anti-inflammatory (Th-2) immune microenvironment through the production of both Th-1 and Th-2 type cytokines upon activation, thus play a vital role in cancer, infection, and autoimmune diseases. Adoptive cell therapy using ex vivo expanded iNKT cells is a promising approach to enhance anti-tumor immunity or immunosuppression. However, overcoming phenotypic and functional heterogeneity and promoting in vivo persistency of iNKT cells remains to be a challenge. Here, we compared various methods for ex vivo expansion of human iNKT cells and assessed the quality of expansion, phenotype, and cytokine production profile of expanded iNKT cells. While a direct stimulation of iNKT cells in peripheral blood mononuclear cells with agonist glycolipid led to the expansion of iNKT cells in varying degrees, stimulation of enriched iNKT cells by irradiated autologous peripheral blood mononuclear cells or allogeneic dendritic cells resulted in consistent expansion of highly pure iNKT cells. Interestingly, the mode of antigenic stimulation influenced the dominant subtype of expanded iNKT cells. Further, we evaluated whether additional IL-7 or IL-15 during antigenic stimulation with allogeneic dendritic cells can improve the phenotypic heterogeneity and modify cytokine production profile of iNKT cells expanded from 18 consecutive donors. The presence of IL-7 or IL-15 during antigenic stimulation did not affect the fold of expansion or purity of expanded iNKT cells. However, IL-7, but not IL-15, led to a better expansion of CD4+ iNKT cells, enhanced Th-2 type cytokine production of CD4+ iNKT cells, and maintained the expansion of central memory (CD45RA-CD62L+) CD4+ iNKT cells. Our results suggest the addition of IL-7 during antigenic stimulation with allogeneic dendritic cells can promote the expansion of CD62L+Th-2+CD4+ human iNKT cells that can be used as novel immunotherapeutic to control excessive inflammation to treat various autoimmune diseases.

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Dendritic Cells Are Critical for the Activation and Expansion of Vδ2⁺ T Cells After Allogeneic Hematopoietic Transplantation.

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OmicsDI is part of the ELIXIR infrastructure

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Dendritic Cells Are Critical for the Activation and Expansion of Vδ2+ T Cells After Allogeneic Hematopoietic Transplantation.

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OmicsDI is part of the ELIXIR infrastructure

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Dendritic Cells Are Critical for the Activation and Expansion of Vδ2⁺ T Cells After Allogeneic Hematopoietic Transplantation.