Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner.
Blood 128(7):1013 (2016)
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inh...
Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival.
Transplant International 29(8):930 (2016)
MyD88 signaling directly promotes T-cell survival and is required for optimal T-cell responses to pathogens. To examine the role of T-cell-intrinsic MyD88 signals in transplantation, we studied mice with targeted T-cell-specific MyD88 deletion. Contrary to expectations, we found that these mice ...
Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.
Journal of Clinical Investigation 126(7):2642 (2016)
Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-...
Immunometabolism of regulatory T cells.
Nature Immunology 17(6):618 (2016)
The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, ho...
Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.
Molecular Genetics and Metabolism 117(2):66 (2016)
The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzy...
Requirement for CD28 in Effector Regulatory T Cell Differentiation, CCR6 Induction, and Skin Homing.
Journal of Immunology 195(9):4154 (2015)
The skin, similar to most nonlymphoid tissues, contains substantial numbers of T cells. Among these, memory T cells serve a sentinel role to protect against pathogens, and regulatory T cells (Tregs) terminate immune responses as a check against unrestrained inflammation. Previously, we created c...
Transplant tolerance: a new role for IL-34.
Journal of Clinical Investigation 125(10):3751 (2015)
Immune-suppressive cell populations, including Tregs and suppressor monocytes, have been implicated in long-term survival of allografts in both human transplant recipients and animal models. The factors that drive differentiation and function of these cell populations are not completely understo...
Tolerance signatures in transplant recipients.
Current Opinion in Organ Transplantation 20(4):400 (2015)
The intent of this review was to describe biomarkers that predict or identify individuals who exhibit tolerance to a transplanted organ. The identification of tolerance biomarkers would spare some individuals the toxicity of immunosuppressive agents, enhance the safety of studies to induce toler...
Basophil expression of diamine oxidase: a novel biomarker of allergen immunotherapy response.
Journal of Allergy and Clinical Immunology 135(4):913 (2015)
Immunotherapy inhibits basophil histamine release, but the assay is cumbersome, and no one has studied the effects of immunotherapy withdrawal.
Intracellular fluorochrome-labeled diamine oxidase (DAO) was used as a novel functional readout of basophil histamine release after immunotherapy. Resul...
Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation.
Science Translational Medicine 7(280):280rv2 (2015)
Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulatin...
Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability.
Nature Immunology 16(2):188 (2015)
Foxp3(+) regulatory T cells (Treg cells) are required for immunological homeostasis. One notable distinction between conventional T cells (Tconv cells) and Treg cells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only Tconv cells downregulate PTEN, the main negativ...
T-cell energy metabolism as a controller of cell fate in transplantation.
Current Opinion in Organ Transplantation 20(1):21 (2015)
To highlight some of the recent developments in the novel field of immunometabolism and the therapeutic potential of the many regulatory components of this immunometabolic network for transplantation.
In response to cytokines, changes in nutrients, and other alterations in the local milieu, immu...
Suppression of T-cell lymphomagenesis in mice requires PTEN phosphatase activity.
Blood 125(5):852 (2015)
Mice with T-cell-specific loss of the tumor suppressor gene PTEN early in T-cell ontogeny develop thymic lymphomas that invariably harbor a reciprocal translocation involving the T-cell receptor α/δ locus and c-myc, t(14;15). In addition to its known function as a lipid phosphatase opposing PI3K...
TIM4 Regulates the Anti-Islet Th2 Alloimmune Response.
Cell Transplantation 24(8):1599 (2015)
The role of the novel costimulatory molecule TIM4 in anti-islet response is unknown. We explored TIM4 expression and targeting in Th1 (BALB/c islets into C57BL/6 mice) and Th2 (BALB/c islets into Tbet(-/-) C57BL/6 mice) models of anti-islet alloimmune response and in a model of anti-islet autoim...
Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.
Journal of Clinical Investigation 125(1):194 (2015)
Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, w...
Homeostatic expansion as a barrier to lymphocyte depletion strategies.
Current Opinion in Organ Transplantation 19(4):357 (2014)
Following lymphodepletion, lymphocytes repopulate the immune space both through enhanced thymopoiesis and proliferation of residual nondepleted peripheral lymphocytes. The term homeostatic proliferation (alternatively homeostatic expansion or lymphopenia-induced proliferation) refers to the latt...
Tolerance: one transplant for life.
Transplantation 98(2):117 (2014)
Recently, The Transplantation Society convened a workshop to address the question, "What do we need to have in place to make tolerance induction protocols a 'standard of care' for organ transplant recipients over the next decade?" In a productive 2-day meeting, there was wide-ranging discussion ...
B cells with immune-regulating function in transplantation.
Nature Reviews: Nephrology 10(7):389 (2014)
In transplantation, the contribution of B cells to the rejection or acceptance of the allograft is a topic of major interest. The presence of donor-specific antibodies in transplant recipients is often associated with decreased graft function and rejection, clearly indicating a pathogenetic role...
Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function.
Cell 157(3):595 (2014)
PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here, we show that PTEN homodimerizes and, in this active conformation, exerts lipid phosphatase activity on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants he...
Signals and pathways controlling regulatory T cells.
Immunological Reviews 258(1):117 (2014)
Induction of specific immune tolerance to grafts remains the sought-after standard following transplantation. Defined by expression of the Foxp3 (forkhead box protein 3) transcription factor, the regulatory T-cell (Treg) lineage has been noted to exert potent immunoregulatory functions that cont...