Biology subjects

Mammadli, M.

Publications and source records attributed to Mammadli, M..

6 recordsLinked to original sources

bioRxiv2021

Wnt/β-catenin regulates alloreactive T cells for the treatment of hematological malignancies

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adaptive immunotherapy. Both the detrimental graft-versus-host disease (GVHD) and the beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we tested a novel mouse model of {beta}-catenin (Cat-Tg) in an allo-HSCT model. Our data show that T cells from Cat-Tg mice did not cause GVHD. Surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing data revealed changes in the expression of over 150 genes for CD4, and over 250 genes for CD8+T cells involved in essential aspects of immune response and GVHD pathophysiology. Transgenic over-expression of human {beta}-catenin primarily affects CD8+ T cell phenotype. Altogether, our data suggest that {beta}-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

immunology↗

bioRxiv2021

TCF-1 in CD4 T cells regulates GVHD severity and persistence

Graft-versus-host disease (GVHD) is a leading cause of mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mature donor T cells in the graft mediate graft-versus-leukemia (GVL) responses against residual tumor cells, which may persist after pre-transplant conditioning regimens. Importantly, the same mature T cells also mediate GVHD. The transcription factor T Cell Factor-1 (TCF-1) is critical for T cell development in the thymus. Using a unique mouse model of allo-HSCT leading to GVHD, we investigated the role of TCF-1 in alloactivated T cell functioning and in GVHD. Here, we report that loss of TCF-1 in mature CD4 T cells reduces GVHD severity and persistence, improving survival of recipient mice. This was due to reduced proliferation, survival, and cytokine production of T cells, as well as increased exhaustion. Gene pathways involved in cytokine response, immune signaling, chemokine signaling, cell cycle, and T cell differentiation were altered by loss of TCF-1 in donor cells. Our companion paper shows that regulation of alloactivated CD4 T cells by TCF-1 differs from regulation of CD8 T cells, suggesting that TCF-1 plays a unique role in each subset. Therefore, targeting of TCF-1 or downstream signaling pathways may be an effective strategy for reducing GVHD following allo-HSCT.

immunology↗

bioRxiv2021

TCF-1 in CD8 T cells separates GVHD from GVL

T Cell Factor-1, encoded by TCF-7, is a transcription factor that plays an essential role during T cell development and differentiation. In this manuscript we utilized a pre-clinical model provided evidence that TCF-7 is dispensable for the anti-tumor response, and that TCF-7 suppresses key transcriptional factors Eomes and T-bet and molecules responsible for peripheral CD8 T cell cytolytic function. We discovered that TCF-7 regulates NKG2D expression on naive and activated mouse CD8 T cells, and that peripheral CD8 T cells from TCF-7 cKO utilize NKG2D to clear tumor cells. We also provide evidence that TCF-7 regulates key signaling molecules, including LCK, LAT, ITK, PLC-{gamma}1, P65, ERKI/II, and JAK/STATs required for peripheral CD8 T cell persistent function. Our data transcriptomic and protein data uncovered the mechanism of how TCF-7 impacting peripheral CD8 T cell inflammatory cytokine production, CD8 T cell activation, and apoptosis. Our pre-clinical model showed that CD8 T cells from TCF-7 cKO mice did not cause GVHD, but effectively cleared primary tumor cells.

immunology↗

bioRxiv2021

Loss of TCF-1 regulates the production of noncanonical Tregs in a prion-like manner

Regulatory T cells (Tregs) are suppressive immune cells used for a variety of clinical and therapeutic applications. Canonical Tregs express CD4, FOXP3, and CD25, which are considered definitive markers of Treg status when used together. However, a subset of noncanonical Tregs expressing only CD4 and FOXP3 have recently been described in some infection contexts. The transcriptional regulation of these cells is still unclear. We found that loss of TCF-1 in all T cells in mice leads to expansion of these cells in multiple tissues in a cell-intrinsic fashion. This effect was not due to aberrant expression of FOXP3, as other functional Treg markers were also expressed. In addition, presence of TCF-1-deficient cells in a chimeric mouse induced increased production of noncanonical Tregs from WT donor cells. Therefore, targeting of TCF-1 may remove suppression on this Treg lineage, increasing the yield of these cells for use in the clinic. Summary sentenceLoss of TCF-1 causes expansion of CD25- FOXP3+ noncanonical Tregs, and TCF-1-deficient T cells induce increased production of CD25- Tregs from WT cells.

immunology↗

bioRxiv2020

Inhibition of ITK differentiates GVT and GVHD in allo-HSCT

Allogeneic hematopoietic stem cell transplantation is a life-saving treatment for many malignant and nonmalignant diseases. Donor T cells contained within the graft prevent tumor recurrence via graft-versus-tumor (GVT) effects, however, also cause graft-versus-host disease (GVHD). Novel treatment strategies are therefore needed to allow maintenance of GVT while suppressing GVHD. Here we show using murine models, that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving the beneficial GVT effects. Donor T cells from Itk-/- mice exhibit significantly reduced production of inflammatory cytokines and migration to GVHD target organs such as liver and small intestine, while maintaining GVT efficacy against primary B-ALL tumors. Itk-/- T cells exhibited reduced expression of IRF4 and decreased JAK/STAT signaling activity, but preserved cytotoxicity, which was accompanied by upregulation of Eomesodermin (Eomes), which was necessary for GVT function. A novel peptide inhibitor ITK signaling is also able to prevent GVHD. This novel peptide inhibitor also reduced cytokine production in mice and human T cells. Altogether, our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVT effects following allo-HSCT treatment. Key PointsO_LIInhibiting ITK by a novel peptide significantly reduces GVHD but retains GVT. C_LIO_LIITK deficient donor T cells exhibit minimal GVHD, but maintain GVT activity. C_LIO_LIITK deficient donor T cells exhibit significantly reduced production of inflammatory cytokines and migration to GVHD target organs. C_LIO_LIEomes is required for GVT effect. C_LI

immunology↗

bioRxiv2019

CrkL is required for donor T cell migration to GvHD Target organs

The success of cancer therapies based on allogeneic hematopoietic stem cell transplant relies on the ability to separate graft-versus-host disease (GvHD) from graft-versus-tumor (GVT) responses. Controlling donor T cell migration into peripheral tissues is a viable option to limit unwanted tissue damage, but a lack of specific targets limits progress on this front. Here, we show that the adaptor protein CrkL, but not the closely related family members CrkI or CrkII, is a crucial regulator of T cell migration. In vitro, CrkL-deficient T cells fail to polymerize actin in response to the integrin ligand ICAM-1, resulting in defective migration. Using a mouse model of GvHD/GVT, we found that while CrkL-deficient T cells can efficiently eliminate hematopoietic tumors they are unable to migrate into inflamed organs, such as the liver and small intestine, and thus do not cause GvHD. These results suggest a specific role for CrkL in trafficking to peripheral organs but not the lymphatic system. In line with this, we found that although CrkL-deficient T cells could clear hematopoietic tumors, they failed to clear the same tumor growing subcutaneously, highlighting the role of CrkL in controlling T cell migration into peripheral tissues. Our results define a unique role for CrkL in controlling T cell migration, and suggest that CrkL function could be therapeutically targeted to enhance the efficacy of immunotherapies involving allogeneic donor cells.

immunology↗