Inhibition of De Novo Autoantibody Production Attenuates Chronic Antibody-Mediated Rejection of Kidney Allografts Despite Maintenance of High Donor-Specific Antibody Titers.

Acute and chronic antibody mediated rejection (ABMR) continues to decrease clinical kidney graft function and survival. Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5 recipients of complete MHC-mismatched A/J kidney allografts with NK cells playing a critical role in the acute ABMR.

Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Unlabelled: Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences.

Failure of Costimulatory Blockade-induced Regulatory T Cells to Sustain Long-term Survival of High Ischemic Allografts.

Background: Costimulatory blockade-induced allograft tolerance has been achieved in rodent models, but these strategies do not translate well to nonhuman primate and clinical transplants. One confounder that may underlie this discrepancy is the greater ischemic inflammation imposed on the transplants. In mice, cardiac allografts subjected to prolonged cold ischemic storage (CIS) before transplant have increased ischemia-reperfusion injury, which amplifies infiltrating endogenous memory CD8 T-cell activation within hours after transplantation to mediate acute graft inflammation and cytotoxic lymphocyte-associated molecule-4 immunoglobulin-resistant rejection.

Neutrophil Cathepsin G Regulates Dendritic Cell Production of IL-12 during Development of CD4 T Cell Responses to Antigens in the Skin.

Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. Sensitization of wild-type (WT) mice induces hapten-reactive effector CD8 T cells producing IFN-γ and IL-17- and IL-4-producing CD4 T cells that cannot mediate CHS. Although CXCR2-dependent Ly6G (neutrophil) cell recruitment into hapten-challenged skin is required to direct effector CD8 T cell infiltration into the challenge site to elicit CHS, 2,4-dinitrofluorobenezene (DNFB) sensitization of CXCR2 mice and neutrophil-depleted WT mice induced both hapten-reactive CD4 and CD8 T cells producing IFN-γ and IL-17.

Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients.

Recent advances in immunosuppressive regimens have decreased acute cellular rejection (ACR) rates and improved intestinal and multivisceral transplant (ITx) recipient survival. We investigated the role of myeloid-derived suppressor cells (MDSCs) in ITx. We identified MDSCs as CD33 CD11b lineage(CD3/CD56/CD19) HLA-DR cells with 3 subsets, CD14 CD15 (e-MDSCs), CD14 CD15 (M-MDSCs), and CD14 CD15 (PMN-MDSCs), in peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the grafted intestinal mucosa.

IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts.

Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil, and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor (IL-1R) signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared with complete MHC-mismatched wild-type cardiac allografts, IL-1R(-/-) allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant, whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased.

Neutrophil expression of Fas ligand and perforin directs effector CD8 T cell infiltration into antigen-challenged skin.

Contact hypersensitivity (CHS) is a T cell response to hapten skin challenge of sensitized individuals proposed to be mediated by hapten-primed CD8 cytolytic T cells. Effector CD8 T cell recruitment into hapten challenge sites to elicit CHS requires prior CXCL1- and CXCL2-mediated neutrophil infiltration into the site. We investigated whether neutrophil activities directing hapten-primed CD8 T cell skin infiltration in response to 2,4-dinitro-1-fluorobenzene (DNFB) required Fas ligand (FasL) and perforin expression.

IL-1 receptor signaling is required at multiple stages of sensitization and elicitation of the contact hypersensitivity response.

Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. The points at which IL-1R signaling is required during this complex, multistep immune response have not been clearly delineated. The role of IL-1R signaling during 2, 4 dinitro-1-fluorobenezene (DNFB) sensitization to induce hapten-specific CD8 effector T cells and in the trafficking of the effector T cells to the DNFB challenge site to elicit the response were investigated using IL-1R deficient mice.

Hapten application to the skin induces an inflammatory program directing hapten-primed effector CD8 T cell interaction with hapten-presenting endothelial cells.

Contact hypersensitivity is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Effector CD8 T cell recruitment into the skin parenchyma to elicit the response to hapten challenge requires prior CXCL1/KC-directed neutrophil infiltration within 3-6 h after challenge and is dependent on IFN-γ and IL-17 produced by the hapten-primed CD8 T cells. Mechanisms directing hapten-primed CD8 T cell localization and activation in the Ag challenge site to induce this early CXCL1 production in response to 2,4-dinitrofluorobenzene were investigated.

CXC chemokine ligand (CXCL) 9 and CXCL10 are antagonistic costimulation molecules during the priming of alloreactive T cell effectors.

Donor Ag-reactive CD4 and CD8 T cell production of IFN-gamma is a principal effector mechanism promoting tissue injury during allograft rejection. The CXCR3-binding chemokines CXCL9 and CXCL10 recruit donor-reactive T cells to the allograft, but their role during the priming of donor-reactive T cells to effector function is unknown. Using a murine model of MHC-mismatched cardiac transplantation, we investigated the influence of CXCL9 and CXCL10 during donor-reactive T cell priming.

CD8 T cells producing IL-17 and IFN-gamma initiate the innate immune response required for responses to antigen skin challenge.

Effector CD8 T cell recruitment into the skin in response to Ag challenge requires prior CXCL1/KC-directed neutrophil infiltration. Mechanisms inducing CXCL1 production and the dynamics of neutrophil-CD8 T cell interactions during elicitation of Ag-specific responses in the skin were investigated. CXCL1 and CXCL2/MIP-2 were produced within 3-6 h of Ag challenge at 10-fold higher levels in skin challenge sites of Ag-sensitized vs nonsensitized mice.

Monokine induced by interferon-gamma (MIG/CXCL9) is derived from both donor and recipient sources during rejection of class II major histocompatibility complex disparate skin allografts.

Chemokines, including monokine induced by interferon-gamma (Mig/CXCL9), are produced both in allografts and during the direct T-cell infiltration that mediates graft rejection. Neither the specific production nor contribution of allograft donor versus recipient Mig in allograft rejection is currently known. C57BL/6 mice with a targeted deletion in the Mig gene were used as both skin allograft donors and recipients in a class II major histocompatibility complex-mismatched graft model to test the requirement for donor- versus recipient-derived Mig for acute rejection.

Regulatory function of CD4+CD25+ T cells from Class II MHC-deficient mice in contact hypersensitivity responses.

Contact hypersensitivity (CHS) is a CD8+ T cell-mediated, inflammatory response to hapten sensitization and challenge of the skin. During sensitization, the magnitude and duration of hapten-specific CD8+ T cell expansion in the skin-draining lymph nodes (LN) are restricted by CD4+CD25+ T regulatory cells (Treg). The regulation of hapten-specific CD8+ T cell priming in Class II MHC-deficient (MHC-/-) mice was investigated.

CD8+ T cells produce IL-2, which is required for CD(4+)CD25+ T cell regulation of effector CD8+ T cell development for contact hypersensitivity responses.

Interleukin (IL)-2 functions to promote, as well as down-regulate, expansion of antigen-reactive CD4+ and CD8+ T cells, but the role of IL-2 in hapten-specific CD8+ T cell priming for contact hypersensitivity (CHS) responses remains untested. Using enzyme-linked immunospot to enumerate numbers of hapten-specific CD4+ and CD8+ T cells producing IL-2 in hapten-sensitized mice, the number of IL-2-producing CD8+ T cells was tenfold that of CD4+ T cells. Hapten-primed CD4+ T cells produced low amounts of IL-2 during culture with hapten-presenting Langerhans cells, whereas production by hapten-primed CD8+ T cells was fivefold greater.

Alloreactive T cell responses and acute rejection of single class II MHC-disparate heart allografts are under strict regulation by CD4+ CD25+ T cells.

Skin but not vascularized cardiac allografts from B6.H-2bm12 mice are acutely rejected by C57BL/6 recipients in response to the single class II MHC disparity. The underlying mechanisms preventing acute rejection of B6.

The intensity of neutrophil infiltration controls the number of antigen-primed CD8 T cells recruited into cutaneous antigen challenge sites.

Recruitment of antigen-specific T cells into the skin is a critical initiating event during immune responses to many parasites and tumors as well as T cell-mediated, cutaneous, allergic responses and autoimmune diseases. Mechanisms directing T cell trafficking into skin remain largely undefined. Here, we show that cutaneous contact with reactive antigen induces KC/CXC chemokine ligand 1 production and neutrophil infiltration in an antigen, dose-dependent manner.

Effects of green tea polyphenols on murine transplant-reactive T cell immunity.

Green tea polyphenols (GrTP), the active ingredient of green tea, may have immunosuppressive properties, but whether and how GrTP affect transplant-reactive T cells is unknown. To address this, we tested the effects of GrTP on in vitro and in vivo transplant-reactive T cell immunity. GrTP inhibited IFNgamma secretion by cultured monoclonal T cells and by alloreactive T cells in mixed lymphocyte reactions.

Absence of allograft ICAM-1 attenuates alloantigen-specific T cell priming, but not primed T cell trafficking into the graft, to mediate acute rejection.

The expression and function of ICAM-1 are critical components in the initiation and elicitation of many T cell-mediated responses. Whether ICAM-1 expression is required on the T cells or on the APC during T cell priming remains unclear. To address this issue in alloantigen-specific T cell activation, the priming and function of T cells in response to heart allografts from MHC-mismatched wild-type vs ICAM-1(-/-) donors were tested.