Granzyme B–Mediated Activation-Induced Death of CD4+ T Cells Inhibits Murine Acute Graft-versus-Host Disease

et al. 2017

OncoImmunology

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Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for hematologic malignancies. Donor T cells are able to eliminate residual tumor cells after allo-HCT, producing the beneficial graft-versus-tumor (GVT) effect, but can also cause graft-versus-host disease (GVHD) when attacking host normal tissues. We previously reported that granzyme B (GzmB) is involved in activation-induced cell death (AICD) of donor T cells and exerts differential impacts on GVHD and GVT effect. Serine protease inhibitor 6 (Spi6) is the sole endogenous inhibitor of GzmB that can protect immune and tissue cells against GzmB-mediated damage. This study is aimed to delineate the mechanism by which the GzmB-Spi6 axis regulates allogeneic T cell response. Using multiple clinically relevant murine allo-HCT models, we have found that Spi6 is concentrated in mitochondria during allogeneic T cell activation, while Spi6 T cells exhibit abnormal mitochondrial membrane potential, mass, reactive oxygen species (ROS) production and increased GzmB-dependent AICD mainly in the form of fratricide. Compared with WT T cells, Spi6 T cells exhibit decreased expansion in the host and cause significantly reduced GVHD. Notably, however, Spi6 T cells demonstrate the same level of GVT activity as WT T cells, which were confirmed by two independent tumor models. In summary, our findings demonstrate that Spi6 plays a novel and critical role in maintaining the integrity of T cell mitochondrial function during allogeneic response, and suggest that disabling Spi6 in donor T cells may represent a novel strategy that can alleviate GVHD without sacrificing the beneficial GVT effect.

Section: E1397247-10mentioning

confidence: 91%

Section: Spi6 Predominantly Protects T Cells From Gzmb-mediated Fratrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serine protease inhibitor 6 protects alloreactive T cells from Granzyme B-mediated mitochondrial damage without affecting graft-versus-tumor effect

Mohammadpour

et al. 2017

OncoImmunology

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“…Mice were sacrificed at days 17, 36, and 66, and large and small intestines were formalin-fixed, sectioned, and stained with H&E. Intestine tissues were examined using a previously established scoring system (23–25). Blinded assessments were made for the presence of crypt epithelial cell apoptosis, crypt regeneration, surface erosion, ulceration, lamina propria inflammation, chronic atrophy, chronic crypt branching, chronic endocrine cell excess, chronic Paneth cell excess, epithelioid vacuolization, attenuation, sloughing into the lumen lymphocytic infiltrate and neutrophilic infiltrate.…”

Section: Methodsmentioning

confidence: 99%

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

The Journal of Immunology

Mohammadpour

et al. 2017

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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.

“…After 3 months, the chimeric hosts were irradiated with 800 cGy and transplanted with 4×10 6 BM alone or combined with 3×10 6 PanT cells isolated from BALB/c donors. Hosts are then monitored for GVHD and survival as previously described (42, 43). …”

Section: Methodsmentioning

confidence: 99%

Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function

Leigh

The Journal of Immunology

et al. 2017

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Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to T cell receptor signaling, co-stimulatory pathways are involved in T cell activation. CD27 is a TNF receptor family member expressed on T cells and its ligand, CD70, is expressed on APCs. The CD27/CD70 co-stimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, antibody blockade of CD70 following allo-HCT significantly increases GVHD. Interestingly, while donor T cell- or BM-derived CD70 plays no role in GVHD, host-derived CD70 inhibits GVHD as CD70-/- hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased histopathologic damage compared to WT hosts. In addition, CD70-/- hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD70-/- versus WT hosts. Mechanistic analyses suggest that CD70 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Together, our findings demonstrate that host CD70 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.