In vitro-generated alloantigen-specific Th9 cells mediate antileukemia cytotoxicity in the absence of graft-versus-host disease

Abstract

Allogeneic bone marrow transplantation (BMT) is a curative therapy for various hematological malignancies, such as leukemias and lymphomas. Donor-derived alloantigenspecific T cells eradicate residual tumor cells, however, these T cells are also responsible for the induction of graftversus-host disease (GVHD). Therefore, one major challenge in BMT is the identification of T-cell subsets provoking antitumor cytotoxicity without causing GVHD. T helper (Th) subsets are programmed into various lineages dependent on ligand interactions and the cytokine milieu [1]. Th9 cells, which can be generated from naïve CD4 cells after activation in the presence of IL-4 and TGF-β are characterized by increased secretion of IL-9 and have been proven to exhibit efficient antitumor capacity especially toward melanomas [2][3][4]. Likewise, a few studies linked the presence of Th9/IL-9 with enhanced solid organ acceptance and decreased GVHD development [5][6][7]. However, the therapeutic effect of adoptive Th9 cell transfer on GVHD development and eradication of tumor cells is currently not well defined.To clarify whether Th9 cells are suitable for donor lymphocyte infusion in BMT settings, we differentiated naïve splenic CD4 + T cells derived from B6 mice on anti-CD3/CD28 coated plates in the presence of IL-4, TGF-β and the TNF-family cytokine TL1A. About 60% of the cells expressed IL-9 intracellulary after 5 days of differentiation and exhibited high IL-9 RNA expression. Expression of the Th1-specific cytokine IFN-γ was undetectable while IL-5, -13 and TNF-α were weakly expressed (Fig. 1a). Most importantly, Tregs were not differentiated, because Foxp3 expression was undetectable (Fig. S1). To clarify the impact of Th9 cells on GVHD induction, we used an allogeneic CD4 + -dependent parent → F1 BMT model with a 50% mismatch for MHC class I and II molecules (B6 → B6D2F1). The alloantigen H-2 d expressed on recipient tissue of lethally irradiated B6D2F1 (H-2 bxd ) mice activates transplanted B6-derived (H-2 b ) donor T cells. Acute, lethal GVHD in this model only develops if the transplant contains mature CD4 + T cells since the transfer of CD8 +

Role and Potential of Different T Helper Cell Subsets in Adoptive Cell Therapy

“…A recent report also showed that an orthogonal receptor with an extracellular domain of the IL-2 receptor and an intracellular domain of the IL-9 receptor increases the antitumor activity of T cells and polarizes them towards a stem cell memory and effector phenotype [ 123 ] ( Figure 3 b). In addition, in a mouse model of leukemia, in vitro polarized Th9 cells for allogenic bone-marrow transplantation achieved tumor eradication without inducing graft-versus-host disease [ 124 ].…”

Regulatory role of T helper 9/interleukin-9: Transplantation view

“…Nevertheless, they can be detected during multiple sclerosis, ulcerative colitis, food allergies, allergic inflammation, asthma, and transplant rejection [ 1 , 6 , 7 ]. Moreover, few studies have confirmed the importance of Th9/IL-9 in organ transplant tolerance [ 8 ]. Therefore, this study aimed to investigate the biological and immunologic characteristics of IL-9, as well as its importance in inflammation.…”

Staphylococcus aureus‐derived factors promote human Th9 cell polarization and enhance a transcriptional program associated with allergic inflammation

“…Th9 cells, first described about a decade ago, are characterized by the potent secretion of IL‐9, a pleiotropic cytokine with both protective and disease‐inducing effects. Functionally, Th9 cells promote anti‐tumor immunity [3, 4] as well as defense against parasitic infections [5], but have also been associated with the pathogenesis of allergic diseases [6, 7]. The transcription factor network controlling Th9 responses is not yet fully understood, and a master gene regulator has so far not been found, as it has for the other Th subsets [8].…”