Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

Veenstra, Rachelle G.; Taylor, Patricia A.; Zhou, Qing; Panoskaltsis‐Mortari, Angela; Hirashima, Mitsuomi; Flynn, Ryan; Liu, Derek; Anderson, Ana C.; Strom, Terry B.; Kuchroo, Vijay K.; Blazar, Bruce R.

doi:10.1182/blood-2011-10-387977

Cited by 51 publications

(45 citation statements)

References 40 publications

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“…Our data (Supplemental Figure 4) showed that blocking TIM-3 shows a trend of making GVHD worse and blocking PD-1 indeed makes GVHD worse, in a fashion similar to CD70 deficiency in donor T cells. These data suggest that these immune checkpoint molecules do have a biological impact in our models, which are consistent with a few previous publications (31–33). …”

Section: Resultssupporting

confidence: 94%

T Cell–Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses

O'Neill

Mohammadpour

et al. 2017

The Journal of Immunology

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The CD27–CD70 pathway is known to provide a costimulatory signal with CD70 expressed on antigen-presenting cells while CD27 functioning on T cells. Although CD70 is also expressed on activated T cells, it remains unclear how T cell-derived CD70 affects T cell function. Therefore, we have assessed the role of T cell-derived CD70 using adoptive transfer models including autoimmune inflammatory bowel disease (IBD) and allogeneic graft-versus-host disease (GVHD). Compared with WT T cells, CD70−/− T cells surprisingly caused more severe IBD and GVHD and produced higher levels of inflammatory cytokines. Mechanistic analyses reveal that IFN-γ induces CD70 expression in T cells, and CD70 limits T cell expansion via a regulatory T cell-independent mechanism that involves caspase-dependent T cell apoptosis and upregulation of inhibitory immune checkpoint molecules. Notably, T cell intrinsic CD70 signaling contributes as least partially to the inhibitory checkpoint function. Overall, our findings demonstrate for the first time that T cell-derived CD70 plays a novel immune checkpoint role in inhibiting inflammatory T cell responses. This study suggests that T cell-derived CD70 performs a critical negative feedback function to downregulate inflammatory T cell responses.

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Section: Resultssupporting

confidence: 94%

T Cell–Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses

O'Neill

Mohammadpour

et al. 2017

The Journal of Immunology

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“…1,2 Other negative regulatory pathways have been shown to play an important role in regulating acute GVHD. [19][20][21][22] Because B7-H3 is a B7 homolog, similar to the PD-1/PD-L1 pathway, it is not surprising that during acute GVHD, B7-H3 would be upregulated in GVHD target organs and that the absence of this inhibitory receptor would accelerate GVHD. 23 Because B7-H3 2/2 donor T cells accelerated GVHD lethality, B7-H3 expression plays a cell-intrinsic role in suppressing T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

Veenstra

Flynn

Kreymborg

et al. 2015

Blood

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Key Points• Absence of B7-H3 expression in allogeneic recipients or on allogeneic donor T cells leads to accelerated GVHD lethality.• Increased GVHD lethality is a result of increased T-cell proliferation, colon inflammatory cytokines, and intestinal permeability.Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3 2/2 vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3 2/2 vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3 2/2 Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications. (Blood. 2015;125(21):3335-3346)

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“…Collectively, these studies employed several different immune system challenges, including mouse models for autoimmunity and autoinflammation [6, 48-54], allotransplantation [55, 48, 56], tolerance induction [6, 48] and allergy [57, 58]. Thus, a substantial body of data has accumulated to support the conclusion that Tim-3 exerts a suppressive effect on Th1 cells.…”

Section: Regulation Of Cd4 T Cell Responses By Tim-3mentioning

confidence: 99%

Regulation of T cell responses by the receptor molecule Tim-3

Gorman

Colgan

2014

Immunol Res

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Tim-3 is a member of the T cell immunoglobulin and mucin domain (Tim) family of proteins, which are expressed by several cell types in the immune system, including CD4 and CD8 T cells activated under certain conditions. These molecules are generally thought to act as receptors for multiple ligands and thus to function by engaging intracellular signaling pathways in a ligand-dependent manner. In recent years, the function of the Tim-3 protein has been studied in some detail, particularly with respect to its role in the regulation of CD4 and CD8 T cell function. Here, we review the structural features of Tim-3, known ligands for this molecule and the links established between Tim-3 and signal transduction pathways. In addition, we review the current literature regarding the role of Tim-3 in the regulation of effector responses by CD4 and CD8 T cells. Overall, findings published thus far strongly support the conclusion that Tim-3 functions to inhibit T cell responses, particularly under conditions involving chronic stimulation. Conversely, some reports have provided evidence that Tim-3 can stimulate T cells under conditions involving acute stimulation, suggesting that the role of Tim-3 may vary depending on context. Further study of Tim-3 is likely to advance our understanding of how CD4 and CD8 T cell responses are regulated and could uncover novel approaches for manipulating T cell function for therapeutic benefit.

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Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

Cited by 51 publications

References 40 publications

T Cell–Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses

T Cell–Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses

B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

Regulation of T cell responses by the receptor molecule Tim-3

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