SHIP-deficient dendritic cells, unlike wild type dendritic cells, suppress T cell proliferation via a nitric oxide-independent mechanism

Background

Dendritic cells (DCs) not only play a crucial role in activating immune cells but also suppressing them. We recently investigated SHIP''s role in murine DCs in terms of immune cell activation and found that TLR agonist-stimulated SHIP−/− GM-CSF-derived DCs (GM-DCs) were far less capable than wild type (WT, SHIP+/+) GM-DCs at activating T cell proliferation. This was most likely because SHIP−/− GM-DCs could not up-regulate MHCII and/or co-stimulatory receptors following TLR stimulation. However, the role of SHIP in DC-induced T cell suppression was not investigated.

Methodology/Principal Findings

In this study we examined SHIP''s role in DC-induced T cell suppression by co-culturing WT and SHIP−/− murine DCs, derived under different conditions or isolated from spleens, with αCD3+ αCD28 activated WT T cells and determined the relative suppressive abilities of the different DC subsets. We found that, in contrast to SHIP+/+ and −/− splenic or Flt3L-derived DCs, which do not suppress T cell proliferation in vitro, both SHIP+/+ and −/− GM-DCs were capable of potently suppressing T cell proliferation. However, WT GM-DC suppression appeared to be mediated, at least in part, by nitric oxide (NO) production while SHIP−/− GM-DCs expressed high levels of arginase 1 and did not produce NO. Following exhaustive studies to ascertain the mechanism of SHIP−/− DC-mediated suppression, we could conclude that cell-cell contact was required and the mechanism may be related to their relative immaturity, compared to SHIP+/+ GM-DCs.

Conclusions

These findings suggest that although both SHIP+/+ and −/− GM-DCs suppress T cell proliferation, the mechanism(s) employed are different. WT GM-DCs suppress, at least in part, via IFNγ-induced NO production while SHIP−/− GM-DCs do not produce NO and suppression can only be alleviated when contact is prevented.     

Disruption of Multivesicular Body Vesicles Does Not Affect Major Histocompatibility Complex (MHC) Class II-Peptide Complex Formation and Antigen Presentation by Dendritic Cells

The antigen processing compartments in antigen-presenting cells (APCs) have well known characteristics of multivesicular bodies (MVBs). However, the importance of MVB integrity to APC function remains unknown. In this study, we have altered the ultrastructure of the MVB by perturbing cholesterol content genetically through the use of a deletion of the lipid transporter Niemann-Pick type C1 (NPC1). Immunofluorescence and electron microscopic analyses reveal that the antigen processing compartments in NPC1^−/− dendritic cells (DCs) have an abnormal ultrastructure in that the organelles are enlarged and the intraluminal vesicles are almost completely absent and those remaining are completely disorganized. MHC-II is restricted to the limiting membrane of these enlarged MVBs where it colocalizes with the peptide editor H2-DM. Curiously, proteolytic removal of the chaperone protein Invariant chain from MHC-II, degradation of internalized foreign antigens, and antigenic-peptide binding to nascent MHC-II are normal in NPC1^−/− DCs. Antigen-pulsed NPC1^−/− DCs are able to effectively activate antigen-specific CD4 T cells in vitro, and immunization of NPC1^−/− mice reveals surprisingly normal CD4 T cell activation in vivo. Our data thus reveal that the localization of MHC-II on the intraluminal vesicles of multivesicular antigen processing compartments is not required for efficient antigen presentation by DCs.     

Deficiency of Autophagy in Dendritic Cells Protects against Experimental Autoimmune Encephalomyelitis

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) in the immune system. DCs present antigens to CD8 and CD4 T cells in the context of class I or II MHC. Recent evidence suggests that autophagy, a conserved intracellular degradation pathway, regulates class II antigen presentation. In vitro studies have shown that deletion of autophagy-related genes reduced antigen presentation by APCs to CD4 T cells. In vivo studies confirmed these findings in the context of infectious diseases. However, the relevance of autophagy-mediated antigen presentation in autoimmunity remains to be elucidated. Here, we report that loss of autophagy-related gene 7 (Atg7) in DCs ameliorated experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-mediated mouse model of multiple sclerosis, by reducing in vivo priming of T cells. In contrast, severity of hapten-induced contact hypersensitivity, in which CD8 T cells and NK cells play major roles, was unaffected. Administration of the autophagy-lysosomal inhibitor chloroquine, before EAE onset, delayed disease progression and, when administered after the onset, reduced disease severity. Our data show that autophagy is required in DCs for induction of EAE and suggest that autophagy might be a potential target for treating CD4 T cell-mediated autoimmune conditions.     

IL-10 Suppression of NK/DC Crosstalk Leads to Poor Priming of MCMV-Specific CD4 T Cells and Prolonged MCMV Persistence

IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the pro-inflammatory cytokines IL-12, IFN-γ and TNF-α as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10 ^−/− mice led to faster control of lytic viral replication, but this came at the expense of TNF-α mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.     

Attenuated Th1 induction by dendritic cells from mice deficient in the leukotriene B4 receptor 1

Dendritic cells (DCs) are important antigen-presenting cells that control Th1- and Th2-type immunological reactions by releasing cytokines and interacting directly with T cells. Leukotriene B4 (LTB4), a classical proinflammatory lipid mediator for phagocytes, was recently identified as an important attractant for effector CD4⁺ and CD8⁺ T cells. However, little information is available on the roles of LTB4 and its receptor BLT1 in DCs. Here we show that functional BLT1 expressed in mouse bone marrow-derived DCs (BMDCs) plays important role in initiating Th1-type immune response. Detailed analyses using BMDCs revealed that BLT1-deficient DCs produced less IL-12p70 than WT DCs, leading to attenuated IFN-γ production in an allogeneic mixed lymphocyte reaction. Adoptive transfer of antigen-loaded BLT1-deficient DCs into naïve WT mice induced a weakened Th1- and enhanced Th2-response in vivo compared to WT DCs. BLT1-deficient mice consistently showed much attenuated delayed-type hypersensitivity (DTH), in which Th1-type cellular responses play a key role, and popliteal lymph node cells of BLT1-deficient mice showed reduced production of Th1 cytokines after DTH induction compared to cells from WT mice. Thus, in addition to its role in inflammation, the LTB4–BLT1 axis is important in initiating Th1-type immunological reactions mediated by DCs.     

Increased CD112 Expression in Methylcholanthrene-Induced Tumors in CD155-Deficient Mice

Tumor recognition by immune effector cells is mediated by antigen receptors and a variety of adhesion and costimulatory molecules. The evidence accumulated since the identification of CD155 and CD112 as ligands for DNAM-1 in humans and mice has suggested that the interactions between DNAM-1 and its ligands play an important role in T cell– and natural killer (NK) cell–mediated recognition and lysis of tumor cells. We have previously demonstrated that methylcholanthrane (MCA) accelerates tumor development in DNAM-1–deficient mice, and the Cd155 level on MCA-induced tumors is significantly higher in DNAM-1–deficient mice than in wild-type (WT) mice. By contrast, Cd112 expression on the tumors is similar in WT and DNAM-1-deficient mice, suggesting that CD155 plays a major role as a DNAM-1 ligand in activation of T cells and NK cells for tumor immune surveillance. To address this hypothesis, we examined MCA-induced tumor development in CD155-deficient mice. Unexpectedly, we observed no significant difference in tumor development between WT and CD155-deficient mice. Instead, we found that Cd112 expression was significantly higher in the MCA-induced tumors of CD155-deficient mice than in those of WT mice. We also observed higher expression of DNAM-1 and lower expression of an inhibitory receptor, TIGIT, on CD8⁺ T cells in CD155-deficient mice. These results suggest that modulation of the expression of receptors and CD112 compensates for CD155 deficiency in immune surveillance against MCA-induced tumors.     

Vaginal Myeloid Dendritic Cells Transmit Founder HIV-1

We report that primary human vaginal dendritic cells (DCs) display a myeloid phenotype and express CD4, CCR5, and CXCR4. Vaginal CD13⁺ CD11c⁺ DCs rapidly and efficiently bound transmitted/founder (T/F) CCR5-tropic (R5) viruses, transported them through explanted vaginal mucosa, and transmitted them in trans to vaginal and blood lymphocytes. Vaginal myeloid DCs may play a key role in capturing and disseminating T/F R5 HIV-1 in vivo and are candidate “gatekeeper” cells in HIV-1 transmission.     

CD8α Dendritic Cells Drive Establishment of HSV-1 Latency

It is generally accepted that CD8 T cells play the key role to maintain HSV-1 latency in trigeminal ganglia of ocularly infected mice. Yet, comparably little is known about the role of innate immunity in establishment of viral latency. In the current study, we investigated whether CD8α DCs impact HSV-1 latency by examining latency in the trigeminal ganglia (TG) of wild-type (WT) C57BL/6 versus CD8α^−/− (lack functional CD8 T cells and CD8α⁺ DCs), CD8β^−/− (have functional CD8α⁺ T cells and CD8α⁺ DCs), and β2m^−/− (lack functional CD8 T cells but have CD8α⁺ DCs) mice as well as BXH2 (have functional CD8 T cells but lack CD8α⁺ DCs) versus WT C3H (have functional CD8α T cells and CD8α⁺ DCs) mice. We also determined whether the phenotype of CD8α^−/− and BXH2 mice could be restored to that of WT mice by adoptive transfer of WT CD8⁺ T cells or bone marrow (BM) derived CD8α⁺ DCs. Our results clearly demonstrate that CD8α DCs, rather than CD8 T cells, are responsible for enhanced viral latency and recurrences.     

Tubulation of Endosomal Structures in Human Dendritic Cells by Toll-like Receptor Ligation and Lymphocyte Contact Accompanies Antigen Cross-presentation

Mouse dendritic cells (DCs) can rapidly extend their Class II MHC-positive late endosomal compartments into tubular structures, induced by Toll-like receptor (TLR) triggering. Within antigen-presenting DCs, tubular endosomes polarize toward antigen-specific CD4⁺ T cells, which are considered beneficial for their activation. Here we describe that also in human DCs, TLR triggering induces tubular late endosomes, labeled by fluorescent LDL. TLR triggering was insufficient for induced tubulation of transferrin-positive endosomal recycling compartments (ERCs) in human monocyte-derived DCs. We studied endosomal remodeling in human DCs in co-cultures of DCs with CD8⁺ T cells. Tubulation of ERCs within human DCs requires antigen-specific CD8⁺ T cell interaction. Tubular remodeling of endosomes occurs within 30 min of T cell contact and involves ligation of HLA-A2 and ICAM-1 by T cell-expressed T cell receptor and LFA-1, respectively. Disintegration of microtubules or inhibition of endosomal recycling abolished tubular ERCs, which coincided with reduced antigen-dependent CD8⁺ T cell activation. Based on these data, we propose that remodeling of transferrin-positive ERCs in human DCs involves both innate and T cell-derived signals.     

Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition of Viral Membrane Gangliosides

Dendritic cells (DCs) are essential antigen-presenting cells for the induction of immunity against pathogens. However, HIV-1 spread is strongly enhanced in clusters of DCs and CD4⁺ T cells. Uninfected DCs capture HIV-1 and mediate viral transfer to bystander CD4⁺ T cells through a process termed trans-infection. Initial studies identified the C-type lectin DC-SIGN as the HIV-1 binding factor on DCs, which interacts with the viral envelope glycoproteins. Upon DC maturation, however, DC-SIGN is down-regulated, while HIV-1 capture and trans-infection is strongly enhanced via a glycoprotein-independent capture pathway that recognizes sialyllactose-containing membrane gangliosides. Here we show that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169), which is highly expressed on mature DCs, specifically binds HIV-1 and vesicles carrying sialyllactose. Furthermore, Siglec-1 is essential for trans-infection by mature DCs. These findings identify Siglec-1 as a key factor for HIV-1 spread via infectious DC/T-cell synapses, highlighting a novel mechanism that mediates HIV-1 dissemination in activated tissues.     

Rapid accumulation of CD14+CD11c+ dendritic cells in gut mucosa of celiac disease after in vivo gluten challenge

Background

Of antigen-presenting cells (APCs) expressing HLA-DQ molecules in the celiac disease (CD) lesion, CD11c⁺ dendritic cells (DCs) co-expressing the monocyte marker CD14 are increased, whereas other DC subsets (CD1c⁺ or CD103⁺) and CD163⁺CD11c⁻ macrophages are all decreased. It is unclear whether these changes result from chronic inflammation or whether they represent early events in the gluten response. We have addressed this in a model of in vivo gluten challenge.

Methods

Treated HLA-DQ2⁺ CD patients (n = 12) and HLA-DQ2⁺ gluten-sensitive control subjects (n = 12) on a gluten-free diet (GFD) were orally challenged with gluten for three days. Duodenal biopsies obtained before and after gluten challenge were subjected to immunohistochemistry. Single cell digests of duodenal biopsies from healthy controls (n = 4), treated CD (n = 3) and untreated CD (n = 3) patients were analyzed by flow cytometry.

Results

In treated CD patients, the gluten challenge increased the density of CD14⁺CD11c⁺ DCs, whereas the density of CD103⁺CD11c⁺ DCs and CD163⁺CD11c⁻ macrophages decreased, and the density of CD1c⁺CD11c⁺ DCs remained unchanged. Most CD14⁺CD11c⁺ DCs co-expressed CCR2. The density of neutrophils also increased in the challenged mucosa, but in most patients no architectural changes or increase of CD3⁺ intraepithelial lymphocytes (IELs) were found. In control tissue no significant changes were observed.

Conclusions

Rapid accumulation of CD14⁺CD11c⁺ DCs is specific to CD and precedes changes in mucosal architecture, indicating that this DC subset may be directly involved in the immunopathology of the disease. The expression of CCR2 and CD14 on the accumulating CD11c⁺ DCs indicates that these cells are newly recruited monocytes.     

CD117+ Dendritic and Mast Cells Are Dependent on RasGRP4 to Function as Accessory Cells for Optimal Natural Killer Cell-Mediated Responses to Lipopolysaccharide

Ras guanine nucleotide-releasing protein-4 (RasGRP4) is an evolutionarily conserved calcium-regulated, guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor. While an important intracellular signaling protein for CD117⁺ mast cells (MCs), its roles in other immune cells is less clear. In this study, we identified a subset of in vivo-differentiated splenic CD117⁺ dendritic cells (DCs) in wild-type (WT) C57BL/6 mice that unexpectedly contained RasGRP4 mRNA and protein. In regard to the biologic significance of these data to innate immunity, LPS-treated splenic CD117⁺ DCs from WT mice induced natural killer (NK) cells to produce much more interferon-γ (IFN-γ) than comparable DCs from RasGRP4-null mice. The ability of LPS-responsive MCs to cause NK cells to increase their expression of IFN-γ was also dependent on this intracellular signaling protein. The discovery that RasGRP4 is required for CD117⁺ MCs and DCs to optimally induce acute NK cell-dependent immune responses to LPS helps explain why this signaling protein has been conserved in evolution.     

Identification of a novel antigen cross‐presenting cell type in spleen

Antigen-presenting cells (APC), like dendritic cells (DC), are essential for T-cell activation, leading to immunity or tolerance. Multiple DC subsets each play a unique role in the immune response. Here, a novel splenic dendritic-like APC has been characterized in mice that has immune function and cell surface phenotype distinct from other, described DC subsets. These were identified as a cell type continuously produced in spleen long-term cultures (LTC) and have an in vivo equivalent cell type in mice, namely ‘L-DC’. This study characterizes LTC-DC in terms of marker phenotype and function, and compares them with L-DC and other known splenic DC and myeloid subsets. L-DC display a myeloid dendritic-like phenotype equivalent to LTC-DC as CD11c^loCD11b^hiMHC-II⁻CD8α⁻ cells, distinct by high accessibility and endocytic capacity for blood-borne antigen. Both LTC-DC and L-DC have strong antigen cross-presentation ability leading to strong activation of CD8⁺ T cells, particularly after exposure to lipopolysaccharide. However, they have weak ability to stimulate CD4⁺ T cells in antigen-specific responses. Evidence is presented here for a novel DC type produced by in vitro haematopoiesis which has distinct antigen-presenting potential and reflects a DC subset present also in vivo in spleen.     

CD83+CCR7+ NK cells induced by interleukin 18 by dendritic cells promote experimental autoimmune uveitis

Natural killer (NK) cells have been reported to play a pathological role in autoimmune uveitis. However, the mechanisms regarding NK cells in uveitis and factors that affect NK‐cell activation in this condition remain unclear. Here, we report that the number of CD3^‐NK1.1⁺CD83⁺CCR7⁺ cells is increased in the inflamed eyes within a mouse model of experimental autoimmune uveitis (EAU), and these cells express elevated levels of NKG2D, CD69 and IFN‐γ. Adoptively transferring CD83⁺CCR7⁺NK cells aggravates EAU symptoms and increases the number of CD4⁺IFN‐γ⁺T cells and dendritic cells (DCs) within the eye. These CD83⁺CCR7⁺NK cells then promote the maturation of DCs and IFN‐γ expression within T cells as demonstrated in vitro. Furthermore, IL‐18, as primarily secreted by DCs in the eyes, is detected to induce CD83⁺CCR7⁺NK cells. In EAU mice, anti‐IL‐18R antibody treatment also decreases retinal tissue damage, as well as the number of infiltrating CD83⁺CCR7⁺NK cells, T cells and DCs in the inflamed eyes and spleens of EAU mice. These results suggest that CD83⁺CCR7⁺NK cells, as induced by IL‐18 that primarily secreted by DCs, play a critical pathological role in EAU. Anti‐IL‐18R antibody might serve as a potential therapeutic agent for uveitis through its capacity to inhibit CD83⁺CCR7⁺NK cells infiltration.     

Murine melanoma-infiltrating dendritic cells are defective in antigen presenting function regardless of the presence of CD4CD25 regulatory T cells

Tumor-infiltrating dendritic cells are often ineffective at presenting tumor-derived antigen in vivo, a defect usually ascribed to the suppressive tumor environment. We investigated the effects of depleting CD4⁺CD25⁺ “natural” regulatory T cells (Treg) on the frequency, phenotype and function of total dendritic cell populations in B16.OVA tumors and in tumor-draining lymph nodes. Intraperitoneal injection of the anti-CD25 monoclonal antibody PC61 reduced Treg frequency in blood and tumors, but did not affect the frequency of tumor-infiltrating dendritic cells, or their expression of CD40, CD86 and MHCII. Tumor-infiltrating dendritic cells from PC61-treated or untreated mice induced the proliferation of allogeneic T cells in vitro, but could not induce proliferation of OVA-specific OTI and OTII T cells unless specific peptide antigen was added in culture. Some proliferation of naïve, OVA-specific OTI T cells, but not OTII T cells, was observed in the tumor-draining LN of mice carrying B16.OVA tumors, however, this was not improved by PC61 treatment. Experiments using RAG1^−/− hosts adoptively transferred with OTI and CD25-depleted OTII cells also failed to show improved OTI and OTII T cell proliferation in vivo compared to C57BL/6 hosts. We conclude that the defective presentation of B16.OVA tumor antigen by tumor-infiltrating dendritic cells and in the tumor-draining lymph node is not due to the presence of “natural” CD4⁺CD25⁺ Treg.     

Preferential control of induced regulatory T cell homeostasis via a Bim/Bcl-2 axis

Apoptosis has an essential role in controlling T cell homeostasis, especially during the contraction phase of an immune response. However, its contribution to the balance between effector and regulatory populations remains unclear. We found that Rag1^−/− hosts repopulated with Bim^−/− conventional CD4⁺ T cells (Tconv) resulted in a larger induced regulatory T cell (iTreg) population than mice given wild-type (WT) Tconv. This appears to be due to an increased survival advantage of iTregs compared with activated Tconv in the absence of Bim. Downregulation of Bcl-2 expression and upregulation of Bim expression were more dramatic in WT iTregs than activated Tconv in the absence of IL-2 in vitro. The iTregs generated following Tconv reconstitution of Rag1^−/− hosts exhibited lower Bcl-2 expression and higher Bim/Bcl-2 ratio than Tconv, which indicates that iTregs were in an apoptosis-prone state in vivo. A significant proportion of the peripheral iTreg pool exhibits low Bcl-2 expression indicating increased sensitivity to apoptosis, which may be a general characteristic of certain Treg subpopulations. In summary, our data suggest that iTregs and Tconv differ in their sensitivity to apoptotic stimuli due to their altered ratio of Bim/Bcl-2 expression. Modulating the apoptosis pathway may provide novel therapeutic approaches to alter the balance between effector T cells and Tregs.     

CD160Ig Fusion Protein Targets a Novel Costimulatory Pathway and Prolongs Allograft Survival

CD160 is a cell surface molecule expressed by most NK cells and approximately 50% of CD8⁺ cytotoxic T lymphocytes. Engagement of CD160 by MHC class-I directly triggers a costimulatory signal to TCR-induced proliferation, cytokine production and cytotoxic effector functions. The role of CD160 in alloimmunity is unknown. Using a newly generated CD160 fusion protein (CD160Ig) we examined the role of the novel costimulatory molecule CD160 in mediating CD4⁺ or CD8⁺ T cell driven allograft rejection. CD160Ig inhibits alloreactive CD8⁺ T cell proliferation and IFN-γ production in vitro, in particular in the absence of CD28 costimulation. Consequently CD160Ig prolongs fully mismatched cardiac allograft survival in CD4^−/−, CD28^−/− knockout and CTLA4Ig treated WT recipients, but not in WT or CD8^−/− knockout recipients. The prolonged cardiac allograft survival is associated with reduced alloreactive CD8⁺ T cell proliferation, effector/memory responses and alloreactive IFN-γ production. Thus, CD160 signaling is particularly important in CD28-independent effector/memory CD8⁺ alloreactive T cell activation in vivo and therefore may serve as a novel target for prevention of allograft rejection.     

HIV and Mature Dendritic Cells: Trojan Exosomes Riding the Trojan Horse?

Exosomes are secreted cellular vesicles that can induce specific CD4⁺ T cell responses in vivo when they interact with competent antigen-presenting cells like mature dendritic cells (mDCs). The Trojan exosome hypothesis proposes that retroviruses can take advantage of the cell-encoded intercellular vesicle traffic and exosome exchange pathway, moving between cells in the absence of fusion events in search of adequate target cells. Here, we discuss recent data supporting this hypothesis, which further explains how DCs can capture and internalize retroviruses like HIV-1 in the absence of fusion events, leading to the productive infection of interacting CD4⁺ T cells and contributing to viral spread through a mechanism known as trans-infection. We suggest that HIV-1 can exploit an exosome antigen-dissemination pathway intrinsic to mDCs, allowing viral internalization and final trans-infection of CD4⁺ T cells. In contrast to previous reports that focus on the ability of immature DCs to capture HIV in the mucosa, this review emphasizes the outstanding role that mature DCs could have promoting trans-infection in the lymph node, underscoring a new potential viral dissemination pathway.     

TIGIT-Fc alleviates acute graft-versus-host disease by suppressing CTL activation via promoting the generation of immunoregulatory dendritic cells

Graft-versus-host disease (GVHD) is the most common complication and major limitation of allogeneic hematopoietic stem cell transplantation. The CD226/TIGIT-CD155 signal is critical for the cross-talk between T cells and dendritic cells (DCs). Studies have shown that blockade of the CD226-CD155 interaction, using an anti-CD226 antibody, can significantly ameliorate GVHD. It has also been reported that a TIGIT-Fc fusion protein exerts immunosuppressive effects by binding to CD155 on DCs. Here, we used a mouse allogeneic acute GVHD model to explore the therapeutic potential and mechanism of action of TIGIT-Fc. C57/BL6 and Balb/c mice were used as hematopoietic cell graft donors and recipients, respectively. In the TIGIT-Fc-treated mice, GVHD symptom occurrence and mortality were delayed compared to that in isotype control group mice. Histopathological analyses revealed that following TIGIT-Fc treatment, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. The percentage of CD8⁺IFN-γ⁺ and CD8⁺ granzyme B⁺ cells significantly decreased in the TIGIT-Fc group. Moreover, treatment with TIGIT-Fc, even after the onset of GVHD, ameliorated symptoms and prolonged survival. TIGIT-Fc also inhibited CD8⁺ T cell activation in vitro; this was dependent on the presence of CD155 on bone marrow-derived dendritic cells (BMDCs) and on IL-10 production. In addition, TIGIT–CD155 ligation triggered both Erk phosphorylation and STAT3 nuclear translocation. These data indicate that TIGIT plays an important role in the development of GVHD and is an ideal molecular target to treat acute GVHD.