Targeting ITK signaling for T cell-mediated diseases

Weeks, Samuel; Harris, Robert G.; Karimi, Mobin

doi:10.1016/j.isci.2021.102842

Cited by 22 publications

(20 citation statements)

References 104 publications

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“…CD8 T cells from TCF-1 cKO mice exhibited innate memory-like phenotype by upregulating CD122, CD44, and effector and central memory phenotypes in mature CD8 T cells critical for GVHD development [33,34]. We also uncovered that CD8 T cells from TCF-1 cKO mice significantly upregulated Eomes and T-bet, two downstream transcription factors which are known to be involved in GVL [28,[35][36][37]. The loss of TCF-1 also led to upregulation of NK cell type 2 receptor (NKG2D).…”

Section: Introductionmentioning

confidence: 69%

TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses

Harris

Mammadli

Hiner

et al. 2022

Cancer Immunol Immunother

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Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during anti-tumor responses. Our data showed that the loss of TCF-1 in CD8 T cells also leads to loss of key stimulatory molecules such as CD28. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet. Using both in vitro and in vivo models, we uncovered how TCF-1 regulates critical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches suggested that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-γ1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulated several critical aspects of T cell function during CD8 T cell response to cancer. Graphical abstract Summary Figure: TCF-1 is required for persistent function of CD8 T cells but dispensable for anti-tumor response. Here, we have utilized a novel mouse model that lacks TCF-1 specifically on CD8 T cells for an allogeneic transplant model. We uncovered a molecular mechanism of how TCF-1 regulates key signaling pathways at both transcriptomic and protein levels. These key molecules included LCK, LAT, ITK, PLC-γ1, p65, ERK I/II, and JAK/STAT signaling. Next, we showed that the lack of TCF-1 impacted phenotype, proinflammatory cytokine production, chemokine expression, and T cell activation. We provided clinical evidence for how these changes impact GVHD target organs (skin, small intestine, and liver). Finally, we provided evidence that TCF-1 regulates NKG2D expression on mouse naïve and activated CD8 T cells. We have shown that CD8 T cells from TCF-1 cKO mice mediate cytolytic functions via NKG2D.

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Section: Introductionmentioning

confidence: 69%

TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses

Harris

Mammadli

Hiner

et al. 2022

Cancer Immunol Immunother

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“…During GVHD, host tissues are damaged by the activity of alloactivated T cells. To determine whether damage to target organs of GVHD (skin, liver, and small intestine) was altered by loss of TCF-7 in donor T cells, we collected organs from mice allotransplanted as described above (Beilhack et al ., 2005; Mammadli et al ., 2021a; Mammadli et al ., 2021d; Weeks et al ., 2021). At day 7 and day 21 post-transplant, we collected pieces of skin, small intestine, and liver from recipient BALB/c mice.…”

Section: Resultsmentioning

confidence: 99%

“…CD8 T cells from TCF-7 cKO mice exhibited innate memory-like phenotype by upregulating CD122, CD44, and effector and central memory phenotypes in mature CD8 T cells critical for GVHD development (Dutt et al, 2011; Huang et al, 2013). We also uncovered that CD8 T cells from TCF-7 cKO mice significantly upregulated Eomes and T-bet, two downstream transcription factors which are known to be involved in GVL (Mammadli et al ., 2021a; Weeks et al, 2021; Zhou et al, 2010). Our data demonstrated that naïve CD8 T cells from TCF-7 cKO mice upregulated NK cell type 2 receptor (NKG2D).…”

Section: Introductionmentioning

confidence: 99%

TCF-7is dispensable for anti-tumor response but required for persistent function of mature CD8 T cells

Harris

Mammadli

A³

et al. 2021

Preprint

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for hematological malignancy due to graft-versus-leukemia (GVL) effects, mediated by alloreactive donor T cells. However, these same donor cells cause graft-versus-host disease (GVHD), a life-threatening complication. During GVHD, donor T cells proliferate, migrate, and produce cytokines, leading to damage of healthy host tissues. Separating the linked processes of GVHD and GVL is critical to improving outcomes. Here we show that TCF-1, a major T cell developmental factor, plays a role in regulation of these processes. Using a mouse model of allo-HSCT leading to GVHD, we found that conditional loss of TCF-1 in mature CD8 T cells separates GVHD from GVL, providing an optimal clinical phenotype. This occurred due to changes in cytokine production, proliferation, cell survival, chemokine receptor expression, and gene expression. Thus, modulation of TCF-1 signaling reduces GVHD severity and persistence, but maintains GVL effects, and could be useful for allo-HSCT or other T cell-mediated disorders. Furthermore, here and in our companion manuscript we show that regulation of mature, alloactivated T cells by TCF-1 differs between CD4 and CD8 T cells, suggesting that TCF-1 is critical for regulation of mature alloactivated T cells, with unique programs in each subset.

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“…This could be explained by differences between alloactivation in vivo and TCR-mediated activation in vitro. Ki-67, a proliferation marker, was also altered by loss of TCF-7, suggesting that CD8 T cells from TCF-7 cKO mice may proliferate more compared to WT CD8 T cells [93]. We also con rmed that CD8 T cells from TCF-7 cKO mice cause less tissue damage to the target organs, and loss of TCF-7 alters chemokine receptor expression both pre-and post-transplant, which could explain why these cells cause less severe GVHD with increased survival of recipient mice [74].…”

Section: Cd8 T Cells [89]mentioning

confidence: 99%