Biomedical subjects

Robert K Chin

Publications and source records attributed to Robert K Chin.

13 recordsLinked to original sources

PubMed2006

NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway.

NF-kappaB2-deficient mice have impaired T and B cell responses. We found, however, that in these mice there was severe infiltration of lymphocytes into multiple organs and increased activity of autoantibodies to peripheral tissue antigens in a manner similar to that of autoimmune regulator-deficient (Aire-deficient) mice. We further demonstrated that NF-kappaB2 was required for thymic Aire gene transcriptional regulation. The Nfkb2(-/-) thymus had distinct cortical and medullar structures, but reduced Aire and target gene expression of peripheral tissue antigens. Engraftment of Nfkb2(-/-) thymic stroma to nude mice recapitulated the autoimmune phenotype of the native Nfkb2(-/-) mice, confirming a key defect in central tolerance. Lymphotoxin beta receptor (LTbetaR) ligation-induced Aire gene expression was also largely abolished in the absence of NF-kappaB2. Thus NF-kappaB2 downstream of LTbetaR plays an important role in the regulation of central tolerance in an Aire-dependent manner.

Animals↗

PubMed2006

Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure.

The development of spontaneous insulin-dependent diabetes mellitus is preceded by the organization of tertiary lymphoid organ (TLO) in situ, but its role in the development of tissue destruction and the cytokines that control such structures have not been fully defined. We have now observed that TNF superfamily 14 (TNFSF14) is upregulated in aged nonobese diabetic (NOD) pancreas with the appearance of TLO. Blockade of TNFSF14 signaling caused a substantial reduction in the expression of lymphotoxin beta receptor (LTbetaR)-controlled migration factors within the islets and disrupts organization of tertiary structures, leading to prevention of diabetes. Consistently, enhancing LTbetaR signaling by transgenic expression of TNFSF14 in the islets of NOD mice rapidly promoted de novo formation of local TLO, resulting in diabetes, even in the absence of draining lymph nodes (LN). Thus, the TNFSF14-LTbetaR pathway appears to be critical in the development and maintenance of TLO for the onset of diabetes.

Animals↗

PubMed2006

Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen.

Ectopic expression of peripherally restricted Ags by medullary thymic epithelial cells (mTECs) is associated with negative selection. Autoimmune regulator (AIRE) is considered to be the master regulator of these Ags. We show in this study that the ectopic expression of type II collagen (CII) in mTECs and the corresponding central tolerance to CII are AIRE independent but lymphotoxin dependent. The failure to properly express CII in mTECs of Lta(-/-) and Ltbr(-/-) mice leads to overt autoimmunity to CII and exquisite susceptibility to arthritis. These findings define the existence of additional pathways of ectopic peripheral Ag expression, parallel to and independent of AIRE, which may cover an extended spectrum of peripheral Ags in the thymus.

Animals↗

PubMed2004

The human BCL6 transgene promotes the development of lymphomas in the mouse.

BCL6, a gene on chromosome 3, band q27, encodes a zinc finger transcriptional repressor that is needed for germinal center formation and has been implicated in the pathogenesis of some human lymphomas when it is mutated or involved in chromosomal rearrangements. To explore further the mechanisms of action of BCL6 in lymphomagenesis, we developed a transgenic mouse model mimicking a common translocation, the t(3, 14)(q27;q32), in human lymphomas. The transgenic mice develop normally and express the transgenic BCL6 protein constitutively in lymphocytes. A small fraction of the animals develop B and T cell lymphomas after a long latency period, but the incidence is dramatically enhanced following administration of N-ethyl-N-nitrosourea, a carcinogen that induces DNA mutations. The N-ethyl-N-nitrosourea-induced lymphomas spread widely, were exclusively T cell, expressed the BCL6 protein, and occurred only in the transgenic mice. Because BCL6 expression has been reported in a number of T cell tumors as well as in the more commonly occurring B cell lymphomas in humans, our transgenic mice provide a model for the study of human lymphomas.

Animals↗

PubMed2004

Priming of naive T cells inside tumors leads to eradication of established tumors.

The tumor barrier comprised of nonantigenic stromal cells may contribute to the failure of tumor rejection. The tumor-necrosis factor superfamily member LIGHT (also known as TNFSF-14) is a ligand of stromal cell-expressed lymphotoxin-beta receptor and T cell-expressed herpes viral entry mediator (HVEM). Here we show that forced expression of LIGHT in the tumor environment induces a massive infiltration of naive T lymphocytes that correlates with an upregulation of both chemokine production and expression of adhesion molecules. Activation of these infiltrating T cells, possibly through HVEM, leads to the rejection of established, highly progressive tumors at local and distal sites. Our study indicates that targeting the tumor barrier may be an effective strategy for cancer immunotherapy.

Animals↗

PubMed2004

A role for lymphotoxin in the acquisition of Ly49 receptors during NK cell development.

NK cells lyse tumor, virus-infected and allogeneic cells through a recognition system involving inhibitory and activating receptors, among which are the Ly49 molecules that recognize MHC class I proteins. To date, little is known about the regulation of Ly49 expression during NK cell development. In this study we report that the acquisition of Ly49 receptors by NK cells is significantly reduced in lymphotoxin (LT) alpha-deficient mice, whereas it is increased in LTalpha transgenic mice. Treating normal mice with LTbetaR-Ig fusion protein reduced Ly49 expression, indicating that regulation of Ly49 receptor expression occurs through the engagement of membrane LT to LTbetaR, and not soluble LT to TNFR. In addition, when LTalpha(-/-) mice were treated exogenously with recombinant IL-15, NK cell numbers as well as Ly49 acquisition were restored to wild-type levels. Finally, using real-time PCR analyses of bone marrow cells obtained from LT-deficient or transgenic mice, we show a direct correlation between LTbetaR activation and increased IL-15 transcription. These data suggest that LTbetaR-mediated signals regulate Ly49 expression at least in part through the activation of IL-15.

Animals↗

PubMed2004

Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection.

A number of studies have suggested B7-H1, a B7 family member, inhibits T cell responses. Therefore, its expression on nonlymphoid tissues has been proposed to prevent T cell-mediated tissue destruction. To test this hypothesis, we generated transgenic mice that expressed B7-H1 on pancreatic islet beta cells. Surprisingly, we observed accelerated rejection of transplanted allogeneic B7-H1-expressing islet beta cells. Furthermore, transgenic B7-H1 expression broke immune tolerance, as some of the mice spontaneously developed T cell-dependent autoimmune diabetes. In addition, B7-H1 expression increased CD8+ T cell proliferation and promoted autoimmunity induction in a T cell adoptive transfer model of diabetes. Consistent with these findings, B7-H1.Ig fusion protein augmented naive T cell priming both in vitro and in vivo. Our results demonstrate that B7-H1 can provide positive costimulation for naive T cells to promote allograft rejection and autoimmune disease pathogenesis.

Adoptive Transfer↗

PubMed2003

Lymphotoxin is required for maintaining physiological levels of serum IgE that minimizes Th1-mediated airway inflammation.

Although elevated levels of IgE in asthmatic patients are strongly associated with lung infiltration by activated T helper (Th) 2 cells, the physiological role of immunoglobulin E (IgE) in the airway remains largely undefined. Lymphotoxin-deficient alpha (LTalpha-/-) mice exhibit increased airway inflammation, paradoxically accompanied by diminished levels of IgE and reduced airway hyperresponsiveness in response to both environmental and induced antigen challenge. The severe lung inflammation in LTalpha-/- mice is Th1 in nature and can be alleviated by IgE reconstitution. Conversely, depletion of IgE in wild-type mice recapitulates the lung pathologies of LTalpha-/- mice. Therefore, this work has revealed that lymphotoxin is essential for IgE production, and a physiological role of IgE in the airway may consist of maintaining the balance of Th1 and Th2 responses to prevent aberrant inflammation.

Animals↗

PubMed2003

Lymphotoxin pathway directs thymic Aire expression.

The autoimmune regulator Aire is a key mediator of central tolerance for peripherally restricted antigens. Its absence in human patients results in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. The cellular signals that regulate Aire expression are undefined. We show here that lymphotoxin signaling is necessary for the expression of Aire and its downstream target genes. The failure of Aire induction in the thymi of lymphotoxin-deficient and lymphotoxin-beta receptor-deficient mice contributes to overt autoimmunity against self antigens normally protected by Aire. Conversely, stimulation of lymphotoxin-beta receptor by agonistic antibody leads to increased expression of Aire and tissue-restricted antigens in both intact thymi and cultured thymic epithelial cell line. These findings define the essential cross-talk between thymocytes and thymic stroma that is required for central tolerance.

Animals↗

PubMed2003

CD4 dependence of gp120IIIB-CXCR4 interaction is cell-type specific.

The HIV-1 envelope protein gp120IIIB is selective for the CXCR4 chemokine receptor and has been shown to induce apoptosis in neurons both in vivo and in vitro. We examined the ability of gp120IIIB to signal through the rat CXCR4 (rCXCR4) receptor and its dependence on the presence of the human CD4 (hCD4) protein in a number of cell systems. SDF-1alpha potently inhibited N-type Ca channels in cultured HEK293 cells expressing both the Ca channel subunits and rCXCR4 receptors. However, gp120IIIB was ineffective in producing either Ca channel inhibition or in blocking the effects of SDF-1alpha. However, when hCD4 was coexpressed with rCXCR4 and Ca channel subunits, gp120IIIB also produced Ca channel inhibition. Similarly, in PC12 cells transfected with the rCXCR4, SDF-1alpha produced mobilization of intracellular Ca, while gp120IIIB was only effective when hCD4 was coexpressed. SDF-1alpha induced endocytosis of Yellow Fluorescent Protein (YFP)-tagged rCXCR4 expressed in PC12 cells, as did gp120IIIB, an effect which was enhanced by hCD4 coexpression. When tagged rCXCR4 was expressed in F-11 cells or in rat DRG neurons, SDF-1alpha produced extensive receptor endocytosis. However, the ability of gp120IIIB to produce endocytosis was dependent on the coexpression of hCD4. Our results demonstrate that the degree of hCD4 dependence of the agonist effects of gp120IIIB at the rCXCR4 receptor is cell-type specific.

Animals↗

PubMed2003

Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues.

CC chemokine ligand 21 (CCL21)/secondary lymphoid chemokine (SLC), a ligand for CC chemokine receptor 7 (CCR7), has been demonstrated to play a vital role in the homing and localization of immune cells to lymphoid tissues, but its role in nonlymphoid tissues largely remains undefined. Here, we provide evidence that CCL21 in lymphoid and nonlymphoid tissues is differentially regulated by lymphotoxin-dependent (LT-dependent) and -independent mechanisms, respectively. This differential regulation is due to the selective regulation of the CCL21-Ser/CCL21a but not the CCL21-Leu/CCL21b gene by the LT and noncanonical NF-kappaB pathways. This alternate pathway, not dependent on LT or lymphocytes, leading to constitutive expression of CCL21 in nonlymphoid tissues, is critical for the initial recruitment of T lymphocytes to peripheral effector sites. CCL21 expression is subsequently further enhanced in a LT-dependent fashion following airway challenge, potentially facilitating a positive feedback loop to attract additional CCR7+ effector cells. These findings establish an essential role for CCL21 in the recruitment of effector T cells to peripheral tissues and suggest that LT-dependent and -independent regulation of CCL21 plays a role in balancing the central and peripheral immune responses between lymphoid and nonlymphoid tissues.

Animals↗

PubMed2002

B cells control the migration of a subset of dendritic cells into B cell follicles via CXC chemokine ligand 13 in a lymphotoxin-dependent fashion.

Certain classes of dendritic cells (DCs) meet rare cognate Ag-specific T and B cells inside primary B cell follicles for the development of germinal centers. However, the mechanisms underlying this coordination are still undefined. Cysteine-rich (CR) domain of the mannose receptor (CR-Fc)(+) DCs are a newly discovered subset of DCs that migrate rapidly into the primary lymphoid follicles from marginal zone after immunization. In this work, we uncover the key role of B cells in the establishment of a microenvironment that allows these DCs to be in the B cell area in a lymphotoxin (LT)-dependent fashion. CR-Fc(+) DCs are absent from the spleens of both LTbetaR- and LTalpha-deficient mice, suggesting that signaling by membrane LT is required for the presence of CR-Fc(+) DCs in the spleen. Interestingly, analysis of mutant mice that lack T, B, or NK cells demonstrates that B cell-derived membrane LT is essential for the unique localization of CR-Fc(+) DCs in the spleen. Using bone marrow transfer and ligand-blocking approaches, we provide evidence that B cell-derived LT acts indirectly on CR-Fc(+) DCs through LTbetaR(+) stromal cells. In analogous fashion to certain Ag-activated T and B cells, CR-Fc(+) DCs, expressing CXCR5, localize to primary lymphoid follicles in response to CXC ligand 13 (B lymphocyte chemoattractant). Together, we propose that B cells play a central role in establishing the chemotactic gradient that attracts not only Ag-activated T and B cells but also Ag-carrying CR-Fc(+) DCs. In turn, CR-Fc(+) DCs and T cells home to B cell follicles to interact with B cells in the developing germinal center.

Animals↗

PubMed2002

Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production.

Peyer's patches (PPs) and/or mesenteric lymph nodes (MLNs) are thought to be essential for immunoglobulin A (IgA) production. We found that the severe IgA deficiency in lymphotoxin-deficient (LT(-/-)) mice could be fully reversed by reconstitution with LT-expressing bone marrow, despite the absence of both LNs and PPs. The number of IgA precursors from LT(-/-) mice was not reduced, and they were able to migrate into the lamina propria (LP) of wild-type mice but not of LTbetaR(-/-) mice. Consistently, lymphoid tissue chemokines and adhesion molecules were reduced within the LP of LTalpha(-/-) and LTbetaR(-/-) mice. IgA deficiency in LTalpha(-/-) mice was reversed by the transplantation of a segment of RAG-1 (recombination-activating gene 1) deficient intestine, which confirmed the dispensability of the MLNs and PPs and the sufficiency of the LT-mediated gut microenvironment for IgA production.

Adoptive Transfer↗