The Role of T Cells in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory decline and cognitive impairment, which is related to hallmark protein aggregates, amyloid-ß (Аß) plaques and neurofibrillary tangles; the latter are accumulated with hyperphosphorylated Tau protein. Immune cells play an important role in AD pathogenesis. Although the role of T cells in AD remains controversial, studies have shown that T cell deficiency is associated with increased AD pathology. In contrast, transplantation of T cells reduces AD pathology. T cells can help B cells generate anti-Ðß antibody to neutralize the toxin of Ðß and hyperphosphorylated Tau. T cells also activate macrophages to phagocytose misfolded proteins including Ðß and Tau. Recent data have also shown that AD animals have a damaged thymic microenvironment, especially thymic epithelial cells (TECs), resulting in decreased T cell numbers, which contribute to AD pathology. Therefore, regulation of T cell regeneration, for example by rejuvenating the thymic microenvironment, has the potential to be used in the treatment of AD.

Administration of Recombinant TAPBPL Protein Ameliorates Collagen-Induced Arthritis in Mice.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease distinguished by synovial hyperplasia and a progressive destruction of joints. T cells are critical players in the pathogenesis of RA. We have previously identified a novel immune checkpoint molecule, TAPBPL, that inhibits T cell functions in vitro. As a model for human RA, we investigated the ability of the TAPBPL protein to ameliorate collagen type II (CII)-induced arthritis (CIA) in mice that were injected with recombinant TAPBPL or a control protein. The mice were analyzed for CIA development, immune cells, and their responses. We found that TAPBPL protein significantly decreased CIA incidence and reduced clinical and pathological arthritis scores, which were related to a lower number of activated CD4 T cells but a greater number of regulatory T cells (Tregs) in the spleen, and a reduction of Th1/Th17 inflammatory cytokines in the joints and serum. Importantly, TAPBPL protein inhibited CII-specific T cell growth and Th1 and Th17 cytokine expression and reduced the production of CII autoantibodies in the serum. Our results suggest that TAPBPL protein can ameliorate CIA in mice and has the potential to be used in the treatment of patients with RA.

Administration of recombinant FOXN1 protein attenuates Alzheimer's pathology in mice.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older adults and characterized by progressive loss of memory and cognitive functions that are associated with amyloid-beta (Aß) plaques and neurofibrillary tangles. Immune cells play an important role in the clearance of Aß deposits and neurofibrillary tangles. T cells are the major component of the immune system. The thymus is the primary organ for T cell generation. T cell development in the thymus depends on thymic epithelial cells (TECs). However, TECs undergo both qualitative and quantitative loss over time. We have previously reported that a recombinant (r) protein containing FOXN1 and a protein transduction domain can increase the number of TECs and subsequently increases the number of T cells in mice. In this study we determined the ability of rFOXN1 to affect cognitive performance and AD pathology in mice. METHODS: Aged 3xTg-AD and APP/PS1 AD mice were injected with rFOXN1 or control protein. Cognitive performance, AD pathology, the thymic microenvironment and immune cells were then analyzed. RESULTS: Administration of rFOXN1 into AD mice improves cognitive performance and reduces Aß plaque load and phosphorylated tau in the brain. This is related to rejuvenating the aged thymic microenvironment, which results in enhanced T cell generation in the thymus, leading to increased number of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aß antibodies in the serum and the brain, and the macrophage phagocytosis of Aß are enhanced in rFOXN1-treated AD mice. CONCLUSIONS: Our results suggest that rFOXN1 protein has the potential to provide a novel approach to treat AD patients.

Comprehensive phenotypic analysis of diverse FOXN1 variants.

BACKGROUND: Thymus hypoplasia due to stromal cell problems has been linked to mutations in several transcription factors, including Forkhead box N1 (FOXN1). FOXN1 supports T-cell development by regulating the formation and expansion of thymic epithelial cells (TECs). While autosomal recessive FOXN1 mutations result in a nude and severe combined immunodeficiency phenotype, the impact of single-allelic or compound heterozygous FOXN1 mutations is less well-defined. OBJECTIVE: With more than 400 FOXN1 mutations reported, their impact on protein function and thymopoiesis remains unclear for most variants. We developed a systematic approach to delineate the functional impact of diverse FOXN1 variants. METHODS: Selected FOXN1 variants were tested with transcriptional reporter assays and imaging studies. Thymopoiesis was assessed in mouse lines genocopying several human FOXN1 variants. Reaggregate thymus organ cultures were used to compare the thymopoietic potential of the FOXN1 variants. RESULTS: FOXN1 variants were categorized into benign, loss- or gain-of-function, and/or dominant-negatives. Dominant negative activities mapped to frameshift variants impacting the transactivation domain. A nuclear localization signal was mapped within the DNA binding domain. Thymopoiesis analyses with mouse models and reaggregate thymus organ cultures revealed distinct consequences of particular Foxn1 variants on T-cell development. CONCLUSIONS: The potential effect of a FOXN1 variant on T-cell output from the thymus may relate to its effects on transcriptional activity, nuclear localization, and/or dominant negative functions. A combination of functional assays and thymopoiesis comparisons enabled a categorization of diverse FOXN1 variants and their potential impact on T-cell output from the thymus.

BTN2A2-Ig protein inhibits the differentiation of pathogenic Th17 cells and attenuates EAE in mice.

Pathogenic Th17 cells play a key role in the pathogenesis of many autoimmune diseases. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is the commonly used animal model for human MS and is characterized by autoreactive CD4+T cells attacking autoantigens in the CNS and causing myelin sheath damage. Although the recombinant BTN2A2-IgG2aFc (BTN2A2-Ig) fusion protein has been shown to inhibit T cell functions in vitro, it's unclear whether BTN2A2-Ig affects pathogenic Th17 cells and EAE development. We show here that BTN2A2-Ig protein attenuates established EAE, as compared with control Ig protein treatment. This is associated with reduced activation and proliferation of T cells in BTN2A2-Ig-treated EAE mice. Furthermore, BTN2A2-Ig protein inhibits the differentiation of CD4 naïve T cells into pathogenic Th17 cells and reduces the expression levels of Th1/Th17 cytokines and the Th1/Th17 pathway related genes and proteins but increases the expression levels of Th2-related genes and proteins. Our studies not only provide new insights into the mechanisms by which BTN2A2-Ig affects T cells, but also have the potential to provide a new strategy to treat MS and other autoimmune diseases.

Recombinant FOXN1 fusion protein increases T cell generation in aged mice.

Background: Although the thymus continues to export T cells throughout life, it undergoes a profound involution/atrophy with age, resulting in decreased numbers of T cells in the older adult, which has direct etiological linkages with many diseases. T cell development in the thymus is dependent on the thymic microenvironment, in which thymic epithelial cells (TECs) are the major component. However, TECs undergo both a qualitative and quantitative loss during aging, which is believed to be the major factor responsible for age-dependent thymic atrophy. FOXN1 plays a critical role in TEC development and adult TECs maintenance. We have previously reported that intrathymic injection of a recombinant (r) protein containing FOXN1 and a protein transduction domain increases the number of TECs in mice, leading to enhanced thymopoiesis. However, intrathymic injection may not be an ideal choice for clinical applications. In this study, we produce a rFOXN1 fusion protein containing the N-terminal of CCR9, FOXN1 and a protein transduction domain. Results: We show here that, when injected intravenously into aged mice, the rFOXN1 fusion protein migrates into the thymus and enhances thymopoiesis, resulting in increased T cell generation in the thymus and increased number of T cells in peripheral lymphoid organ. Conclusions: Our results suggest that the rFOXN1 fusion protein has the potential to be used in preventing and treating T cell immunodeficiency in the older adult.

Recombinant CD300c-Ig fusion protein attenuates collagen-induced arthritis in mice.

OBJECTIVES: RA is a chronic autoimmune disease characterized by joint inflammation and tissue destruction. Immune responses mediated by T cells and autoantibodies are known to play critical roles in RA. Collagen type II (CII)-induced arthritis (CIA) is a commonly used animal model of human RA. We have previously reported the identification of a new T cell inhibitory molecule CD300c. Here we investigate the ability of recombinant CD300c-IgG2a Fc (CD300c-Ig) fusion protein to prevent and treat CIA. METHODS: Mice were induced to develop CIA by CII and injected with CD300c-Ig or control Ig protein before or after CIA symptoms occur. The mice were examined for CIA clinical and pathological scores, and analysed for the expression of proinflammatory cytokines, the percentage and activation of CD4 T cells and regulatory T cells, CII-specific T cell proliferation and cytokine production, and CII-specific autoantibody production. RESULTS: In a prevention model, CD300c-Ig significantly decreases CIA incidence, and reduces clinical and pathological arthritis scores. In the treatment model, CD300c-Ig ameliorates established CIA. The beneficial effects of CD300c-Ig are related to decreased expansion and activation of T cells in the spleen and reduced expression of proinflammatory cytokines in the joints. CD300c-Ig also inhibits CII-specific T cell proliferation and Th1 and Th17 cytokine production. In addition, CD300c-Ig treatment reduced the production of CII autoantibodies in the serum. Furthermore, CD300c-Ig inhibits the proliferation and activation of T cells from RA patients in vitro. CONCLUSION: CD300c-Ig protein has the potential to be used in the treatment of patients with RA.

Interleukin-17A in Alzheimer's Disease: Recent Advances and Controversies.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that mainly affects older adults. Although the global burden of AD is increasing year by year, the causes of AD remain largely unknown. Numerous basic and clinical studies have shown that interleukin-17A (IL-17A) may play a significant role in the pathogenesis of AD. A comprehensive assessment of the role of IL-17A in AD would benefit the diagnosis, understanding of etiology and treatment. However, over the past decade, controversies remain regarding the expression level and role of IL-17A in AD. We have incorporated newly published researches and point out that IL-17A expression levels may vary along with the development of AD, exercising different roles at different stages of AD, although much more work remains to be done to support the potential role of IL-17A in AD-related pathology. Here, it is our intention to review the underlying mechanisms of IL-17A in AD and address the current controversies in an effort to clarify the results of existing research and suggest future studies.

Gingival mesenchymal stem cell-derived exosomes are immunosuppressive in preventing collagen-induced arthritis.

Due to the unsatisfied effects of clinical drugs used in rheumatoid arthritis (RA), investigators shifted their focus on the biotherapy. Although human gingival mesenchymal stem cells (GMSC) have the potential to be used in treating RA, GMSC-based therapy has some inevitable side effects such as immunogenicity and tumorigenicity. As one of the most important paracrine mediators, GMSC-derived exosomes (GMSC-Exo) exhibit therapeutic effects via immunomodulation in a variety of disease models, bypassing potential shortcomings of the direct use of MSCs. Furthermore, exosomes are not sensitive to freezing and thawing, and can be readily available for use. GMSC-Exo has been reported to promote tissue regeneration and wound healing, but have not been reported to be effective against autoimmune diseases. We herein compare the immunomodulatory functions of GMSC-Exo and GMSC in collagen-induced arthritis (CIA) model and in vitro CD4+ T-cell co-culture model. The results show that GMSC-Exo has the same or stronger effects compared with GMSC in inhibiting IL-17A and promoting IL-10, reducing incidences and bone erosion of arthritis, via inhibiting IL-17RA-Act1-TRAF6-NF-κB signal pathway. Our results suggest that GMSC-Exo has many advantages in treating CIA, and may offer a promising new cell-free therapy strategy for RA and other autoimmune diseases.

Administration of anti-ERMAP antibody ameliorates Alzheimer's disease in mice.

BACKGROUND: Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aß) plaques. Immune cells play an important role in the clearance of Aß deposits. Immune responses are regulated by immune regulators in which the B7 family members play a crucial role. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions. METHODS: We produced a monoclonal antibody (mAb) against ERMAP protein and then determined the ability of the mAb to affect cognitive performance and AD pathology in mice. RESULTS:  We have shown that the anti-ERMAP mAb neutralizes the T cell inhibitory activity of ERMAP and enhances macrophages to phagocytose Aß in vitro. Administration of the mAb into AD mice improves cognitive performance and reduces Aß plaque load in the brain. This is related to increased proportion of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aß antibodies in the serum and the macrophage phagocytosis of Aß are enhanced in the anti-ERMAP mAb-treated AD mice. CONCLUSIONS: Our results suggest that manipulating the ERMAP pathway has the potential to provide a novel approach to treat AD patients.

BTN2A2 protein negatively regulates T cells to ameliorate collagen-induced arthritis in mice.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by persistent inflammatory responses in target tissues and organs, resulting in the destruction of joints. Collagen type II (CII)-induced arthritis (CIA) is the most used animal model for human RA. Although BTN2A2 protein has been previously shown to inhibit T cell functions in vitro, its effect on autoimmune arthritis has not been reported. In this study, we investigate the ability of a recombinant BTN2A2-IgG2a Fc (BTN2A2-Ig) fusion protein to treat CIA. We show here that administration of BTN2A2-Ig attenuates established CIA, as compared with control Ig protein treatment. This is associated with reduced activation, proliferation and Th1/Th17 cytokine production of T cells in BTN2A2-Ig-treated CIA mice. BTN2A2-Ig also inhibits CII-specific T cell proliferation and Th1/Th17 cytokine production. Although the percentage of effector T cells is decreased in BTN2A2-Ig-treated CIA mice, the proportions of naive T cells and regulatory T cells is increased. Furthermore, BTN2A2-Ig reduces the percentage of proinflammatory M1 macrophages but increases the percentage of anti-inflammatory M2 macrophages in the CIA mice. Our results suggest that BTN2A2-Ig protein has the potential to be used in the treatment of collagen-induced arthritis models.

Identification of TAPBPL as a novel negative regulator of T-cell function.

T cell stimulatory and inhibitory molecules are critical for the regulation of immune responses. In this study, we identify a novel T cell co-inhibitory molecule TAPBPL, whose amino acid sequence shares homology with known B7 family members. TAPBPL protein is expressed on resting and activated T cells, B cells, monocytes, and dendritic cells (DCs), as well as on some tumor tissues. The putative TAPBPL receptor is expressed on activated CD4 and CD8 T cells. A soluble recombinant human TAPBPL-IgG Fc (hTAPBPL-Ig) fusion protein inhibits the proliferation, activation, and cytokine production of both mouse and human T cells in vitro. In vivo administration of hTAPBPL-Ig protein attenuates experimental autoimmune encephalomyelitis (EAE) in mice. Furthermore, an anti-TAPBPL monoclonal antibody neutralizes the inhibitory activity of hTAPBPL-Ig on T cells, enhances antitumor immunity, and inhibits tumor growth in animal models. Our results suggest that therapeutic intervention of the TAPBPL inhibitory pathway may represent a new strategy to modulate T cell-mediated immunity for the treatment of cancer, infections, autoimmune diseases, and transplant rejection.

ERMAP is a B7 family-related molecule that negatively regulates T cell and macrophage responses.

T cell activation and tolerance are tightly regulated by costimulatory and coinhibitory molecules. B7 family members play a crucial role in regulating immune responses. In this study, we identified erythroid membrane-associated protein (ERMAP) as a novel T cell inhibitory molecule. ERMAP shares significant sequence and structural homology with existing B7 family members in its extracellular domain. The ERMAP protein is expressed on the cell surface of resting and activated antigen-presenting cells (APCs) and in some tumor tissues. The putative ERMAP receptor is expressed on activated CD4 and CD8 T cells and macrophages. Both mouse and human ERMAP-IgG2a Fc (ERMAP-Ig) fusion proteins inhibit T cell functions in vitro. Administration of ERMAP-Ig protein ameliorates autoimmune diseases, including experimental autoimmune encephalomyelitis and type 1 diabetes, in mice. Anti-ERMAP antibody enhances macrophage phagocytosis of cancer cells in vitro. Furthermore, administration of an anti-ERMAP antibody inhibits tumor growth in mice likely by blocking the inhibitory effects of ERMAP on T cells and macrophages. Our results suggest that therapeutic interaction with the ERMAP inhibitory pathway may represent a novel strategy for treating patients with autoimmune disease or cancer.

Administration of Amyloid Precursor Protein Gene Deleted Mouse ESC-Derived Thymic Epithelial Progenitors Attenuates Alzheimer's Pathology.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia in older adults. Although amyloid-beta (Aß) plaque deposition and chronic neuroinflammation in the central nervous system (CNS) contribute to AD pathology, neither Aß plaque removal nor anti-inflammatory therapy has shown much clinical success, suggesting that the combinational therapies for the disease-causative factors may be needed for amelioration. Recent data also suggest that systemic immunity in AD should be boosted, rather than suppressed, to drive an immune-dependent cascade needed for Aß clearance and brain repair. Thymic epithelial cells (TECs) not only play a critical role in supporting T cell development but also mediate the deletion of autoreactive T cells by expressing autoantigens. We have reported that embryonic stem cells (ESCs) can be selectively induced to differentiate into thymic epithelial progenitors (TEPs) in vitro that further develop into TECs in vivo to support T cell development. We show here that transplantation of mouse ESC (mESC)-TEPs into AD mice reduced cerebral Aß plaque load and improved cognitive performance, in correlation with an increased number of T cells, enhanced choroid plexus (CP) gateway activity, and increased number of macrophages in the brain. Furthermore, transplantation of the amyloid precursor protein (APP) gene deleted mESC-TEPs (APP-/-) results in more effective reduction of AD pathology as compared to wild-type (APP+/+) mESC-TEPs. This is associated with the generation of Aß-specific T cells, which leads to an increase of anti-Aß antibody (Ab)-producing B cells in the spleen and enhanced levels of anti-Aß antibodies in the serum, as well as an increase of Aß phagocytosing macrophages in the CNS. Our results suggest that transplantation of APP-/- human ESC- or induced pluripotent stem cell (iPSC)-derived TEPs may provide a new tool to mitigate AD in patients.

Changes of immune parameters of T lymphocytes and macrophages in EAE mice after BM-MSCs transplantation.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration, demyelination and axonal injury. Mesenchymal stem cells (MSCs) are pluripotent which can not only differentiate into many types of cells, but also have immunomodulatory effects. We show here that the transplantation of bone marrow MSCs (BM-MSCs) prevents the development of experimental autoimmune encephalomyelitis (EAE), the most common animal model of MS. Furthermore, we demonstrate that the immunologic mechanism by which BM-MSC transplantation ameliorates EAE involves inhibiting the proliferation and activation of T cells, reducing the production of inflammatory cytokines, and regulating macrophage responses, especially the macrophage polarization. The findings broaden our understanding about the regulation of T cell and macrophage immune responses by MSC transplantation.

Transplantation of MHC-mismatched mouse embryonic stem cell-derived thymic epithelial progenitors and MHC-matched bone marrow prevents autoimmune diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-secreting islet ß cells by autoreactive T cells. Non-obese diabetic (NOD) mice are the widely used animal model for human T1D. Autoimmunity in NOD mice is associated with particular major histocompatibility complex (MHC) loci and impaired islet autoantigen expression and/or presentation in the thymus, which results in defects in both central and peripheral tolerance. It has been reported that induction of mixed chimerism with MHC-mismatched, but not MHC-matched donor bone marrow (BM) transplants prevents the development T1D in NOD mice. We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to generate thymic epithelial progenitors (TEPs) that further develop into thymic epithelial cells (TECs) in vivo to support T cell development. METHODS: To determine whether transplantation of MHC-mismatched mESC-TEPs could prevent the development of insulitis and T1D, NOD mice were conditioned and injected with MHC-mismatched B6 mESC-TEPs and MHC-matched BM from H-2g7 B6 mice. The mice were monitored for T1D development. The pancreas, spleen, BM, and thymus were then harvested from the mice for evaluation of T1D, insulitis, chimerism levels, and T cells. RESULTS: Transplantation of MHC-mismatched mESC-TEPs and MHC-matched donor BM prevented insulitis and T1D development in NOD mice. This was associated with higher expression of proinsulin 2, a key islet autoantigen in the mESC-TECs, and an increased number of regulatory T cells. CONCLUSIONS: Our results suggest that embryonic stem cell-derived TEPs may offer a new approach to control T1D.

Skint8, a Novel B7 Family-Related Molecule, Negatively Regulates T Cell Responses.

Immune responses are tightly controlled by T cell costimulatory and coinhibitory molecules. In this study, we identify Skint8 as a new member of the T cell coinhibitory group, whose extracellular domains share significant homology with existing B7 family members. Skint8 mRNA is expressed in resting and activated B cells, monocytes, and CD4 T cells. The Skint8 putative receptor is expressed on activated CD4 and CD8 T cells, B cells, monocytes and dendritic cells. Recombinant Skint8-IgG Fc fusion protein inhibits T cell proliferation, activation, and cytokine production in vitro. In vivo administration of Skint8-IgG Fc reduces T cell activation and alleviates experimental autoimmune encephalomyelitis in mice. The findings broaden our understanding of the regulation of immune responses and may have implications for treating immune-related diseases.

BTNL2-Ig Protein Attenuates Type 1 Diabetes in Non-Obese Diabetic (NOD) Mice.

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease in which insulin-producing ß-cells are destroyed. Although butyrophilin-like 2 (BTNL2) has been shown to be a negative T cell regulator in vitro, its ability to inhibit T cell responses in vivo has not been determined. In this study, the effect of a recombinant BTNL2-IgG2a Fc (rBTNL2-Ig) fusion protein on T1D development in vivo is determined. It is shown here that in vivo administration of rBTNL2-Ig ameliorates T1D in non-obese diabetic (NOD) mice. This is associated with the ability of rBTNL2-Ig to inhibit the proliferation, activation, and inflammatory cytokine production from autoreactive T cells in vivo. In addition, rBTNL2-Ig treatment increases the generation of regulatory T cells. The results suggest that targeting the BTNL2 pathway has the potential to be used in the prevention and treatment of patients with T1D.

In vivo administration of recombinant BTNL2-Fc fusion protein ameliorates graft-versus-host disease in mice.

Although hematopoietic stem cell transplantation (HSCT) has been widely used in the treatment of many diseases, graft-versus-host disease (GVHD) remains a major complication after allogeneic HSCT. Butyrophilin-like 2 (BTNL2) protein has been reported to have the ability to inhibit T cell proliferation in vitro; its ability to inhibit T cell responses in vivo has not been determined. We show here that in vivo administration of recombinant BTNL2-IgG2a Fc (rBTNL2-Ig) fusion protein ameliorates GVHD in mice. This is related to the ability of rBTNL2-Ig to inhibit T cell proliferation, activation and Th1/Th17 cytokine production in vivo. Furthermore, rBTNL2-Ig treatment increases the generation of regulatory T cells. Our results suggest that rBTNL2-Ig has the potential to be used in the prevention and treatment of patients with GVHD.

A CD300c-Fc Fusion Protein Inhibits T Cell Immunity.

T cell responses are fine-tuned by co-stimulatory and co-inhibitory molecules. Among the T cell regulators, the B7 family members are of central importance. The recent success in targeting the B7 family molecules for the treatment of immune-related diseases has attracted intense interest in identifying additional B7-related molecules. In this study, we describe CD300c as a novel T cell co-inhibitory molecule that shares significant sequence homology with existing B7 family members. CD300c protein is expressed on professional antigen-presenting cells (APC), including B cells, monocytes, macrophages, and dendritic cells (DCs). The putative CD300c counter-receptor is expressed on CD4 and CD8 T cells, and the expression levels are upregulated upon activation. Soluble human and mouse CD300c-Fc fusion proteins significantly inhibit the proliferation, activation, and cytokine production by CD4 and CD8 T cells in vitro. Administration of CD300c-Fc protein attenuates graft-vs.-host disease (GVHD) in mice. Our results suggest that therapeutic interaction with the CD300c inhibitory pathway may represent a new strategy to modulate T cell-mediated immunity for the treatment of GVHD and autoimmune disease.