The impact of bone cell activation on bacterially-induced osteolysis remains elusive. Here, we sh... more The impact of bone cell activation on bacterially-induced osteolysis remains elusive. Here, we show that matrix-embedded osteocytes stimulated with bacterial pathogen-associated molecular patterns (PAMPs) directly drive bone resorption through an MYD88-regulated signaling pathway. Mice lacking MYD88, primarily in osteocytes, protect against osteolysis caused by calvarial injections of bacterial PAMPs and resist alveolar bone resorption induced by oral Porphyromonas gingivalis (Pg) infection. In contrast, mice with targeted MYD88 restoration in osteocytes exhibit osteolysis with inflammatory cell infiltration. In vitro, bacterial PAMPs induce significantly higher expression of the cytokine RANKL in osteocytes than osteoblasts. Mechanistically, activation of the osteocyte MYD88 pathway up-regulates RANKL by increasing binding of the transcription factors CREB and STAT3 to Rankl enhancers and by suppressing K48-ubiquitination of CREB/CREB binding protein and STAT3. Systemic administrat...
We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on hu... more We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on human CD4+ T cells and up-regulate T-cell receptor (TCR) triggered-Th1 responses in vitro and in vivo. To better understand the role of T-cell expressed TLR2 on CD4+ T cell differentiation and function, we conducted a gene expression analysis of naïve CD4+ T-cells stimulated in the presence or absence of TLR2 co-stimulation. Unexpectedly, naïve CD4+ T-cells co-stimulated via TLR2 show a significant up-regulation of IL-9 mRNA compared to cells co-stimulated via CD28. To further evaluate the impact of T-cell expressed TLR2 on TH9 differentiation, naïve CD4+ T cells were polyclonally stimulated under TH9 polarizing conditions with or without a TLR2 agonist. Upregulation of TH9 differentiation, evidenced by increases in both percent of IL-9 secreting cells and IL-9 in culture supernatants, was observed in cells differentiated in the presence of TLR2 agonist. Also, engagement of T-cell TLR2 up-...
Tuberculosis (TB) is the leading cause of mortality among those infected with human immunodeficie... more Tuberculosis (TB) is the leading cause of mortality among those infected with human immunodeficiency virus (HIV-1) worldwide. HIV-1 load and heterogeneity are increased both locally and systemically in active TB. Mycobacterium tuberculosis (MTB) infection supports HIV-1 replication through dysregulation of host cytokines, chemokines, and their receptors. However the possibility that mycobacterial molecules released from MTB infected macrophages directly interact with CD4+ T cells triggering HIV-1 replication has not been fully explored. We studied the direct effect of different MTB molecules on HIV-1 replication (R5-tropic strain Bal) in anti-CD3- stimulated CD4 T cells from healthy donors in an antigen+ presenting cell (APC)-free system. PIM, a major glycolipid of the mycobacterial cell wall, induced significant increases in the6 percent of HIV-1 infected T cells and the viral production in culture supernatants. In spite of structural relatedness, none of the other three major MTB ...
Although a role for TLR2 on T cells has been indicated in prior studies, in vivo stimulation of T... more Although a role for TLR2 on T cells has been indicated in prior studies, in vivo stimulation of TLR2 on T cells by Mtb and its impact on Mtb infection has not been tested. Furthermore, it is not known if the enhanced susceptibility to Mtb of Tlr2 gene knockout (ko) mice is due to its role in macrophages, on T cells or both. To address TLR2 on T cells, we generated Tlr2fl/flxCd4cre/cre mice, which lack expression of TLR2 on both CD4 and CD8 T cells, to study the in vivo role of TLR2 on T cells after aerosol infection with virulent Mtb. Deletion of TLR2 in CD4+ and CD8+ T cells reduces their ability to be co-stimulated by TLR2 ligands for cytokine production. These include both pro-(IFN-γ, TNF-α) and anti-inflammatory cytokines (IL-10). Deletion of TLR2 in T cells did not affect early control but did result in decreased late control of Mtb in the lungs of infected mice. This suggests that T cell co-stimulation by mycobacterial TLR2 ligands in vivo is important for control of infection...
Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust adapti... more Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust adaptive CD4+ T-cell responses. We have previously shown that M. tuberculosis can indirectly inhibit CD4+ T cells by suppressing the major histocompatibility complex class II antigen-presenting cell function of macrophages. This study was undertaken to determine if M. tuberculosis could directly inhibit CD4+ T-cell activation. Murine CD4+ T cells were purified from spleens by negative immunoaffinity selection followed by flow sorting. Purified CD4+ T cells were activated for 16 to 48 h with CD3 and CD28 monoclonal antibodies in the presence or absence of M. tuberculosis and its subcellular fractions. CD4+ T-cell activation was measured by interleukin 2 production, proliferation, and expression of activation markers, all of which were decreased in the presence of M. tuberculosis. Fractionation identified that M. tuberculosis cell wall glycolipids, specifically, phosphatidylinositol mannoside an...
Mycobacterium tuberculosis resides in phagosomes inside macrophages. In this study, we analyzed t... more Mycobacterium tuberculosis resides in phagosomes inside macrophages. In this study, we analyzed the kinetics and location of M. tuberculosis peptide-major histocompatibility complex class II (MHC-II) complexes in M. tuberculosis-infected human macrophages. M. tuberculosis peptide-MHC-II complexes were detected with polyclonal autologous M. tuberculosis-specific CD4+ T cells or F9A6 T hybridoma cells specific for M. tuberculosis antigen (Ag) 85B (96-111). Macrophages processed heat-killed M. tuberculosis more rapidly and efficiently than live M. tuberculosis. To determine where M. tuberculosis peptide-MHC-II complexes were formed intracellularly, macrophages incubated with heat-killed M. tuberculosis were homogenized, and subcellular compartments were separated on Percoll density gradients analyzed with T cells. In THP-1 cells, M. tuberculosis Ag 85B (96- 111)-DR1 complexes appeared initially in phagosomes, followed by MHC class II compartment (MIIC) and the plasma membrane fractions...
Mycobacterium tuberculosis survives in macrophages in the face of acquired CD4+ T-cell immunity, ... more Mycobacterium tuberculosis survives in macrophages in the face of acquired CD4+ T-cell immunity, which controls but does not eliminate the organism. Gamma interferon (IFN-γ) has a central role in host defenses against M. tuberculosis by activating macrophages and regulating major histocompatibility complex class II (MHC-II) antigen (Ag) processing. M. tuberculosis interferes with IFN-γ receptor (IFN-γR) signaling in macrophages, but the molecules responsible for this inhibition are poorly defined. This study determined that the 19-kDa lipoprotein from M. tuberculosis inhibits IFN-γ-regulated HLA-DR protein and mRNA expression in human macrophages. Inhibition of HLA-DR expression was associated with decreased processing and presentation of soluble protein Ags and M. tuberculosis bacilli to MHC-II-restricted T cells. Inhibition of HLA-DR required prolonged exposure to 19-kDa lipoprotein and was blocked with a monoclonal antibody specific for Toll-like receptor 2 (TLR-2). The 19-kDa li...
Vγ9Vδ2+ T cells (γδ T cells) are activated by Mycobacterium tuberculosis and recognize mycobacter... more Vγ9Vδ2+ T cells (γδ T cells) are activated by Mycobacterium tuberculosis and recognize mycobacterial nonpeptide phosphoantigens. The role of antigen-presenting cells in the processing and presentation of phosphoantigens to Vγ9Vδ2+ T cells is not understood. We analyzed the role of macrophages for activation of γδ T cells by a new synthetic phosphoantigen bromohydrin pyrophosphate (BrHPP) and M. tuberculosis. Macrophages greatly increased γδ T-cell activation by both BrHPP and M. tuberculosis. Fixation of macrophages before infection demonstrated that uptake of M. tuberculosis was required for presentation to γδ T cells. Antigens of M. tuberculosis remained stably associated with macrophage surface and were not removed by paraformaldehyde fixation or washing. Macrophages processed M. tuberculosis for γδ T cells through a brefeldin A-insensitive pathway, suggesting that transport through the endoplasmic reticulum and Golgi complex of a putative presenting molecule is not important in ...
ABSTRACTThe success ofMycobacterium tuberculosisas a pathogen relies on its ability to regulate t... more ABSTRACTThe success ofMycobacterium tuberculosisas a pathogen relies on its ability to regulate the host immune response.M. tuberculosiscan manipulate adaptive T cell responses indirectly by modulating antigen-presenting cell (APC) function or by directly interacting with T cells. Little is known about the role ofM. tuberculosismolecules in direct regulation of T cell function. Using a biochemical approach, we identified lipoproteins LprG and LpqH as major molecules inM. tuberculosislysate responsible for costimulation of primary human CD4+T cells. In the absence of APCs, activation of memory CD4+T cells with LprG or LpqH in combination with anti-CD3 antibody induces Th1 cytokine secretion and cellular proliferation. Lipoprotein-induced T cell costimulation was inhibited by blocking antibodies to Toll-like receptor 2 (TLR2) and TLR1, indicating that human CD4+T cells can use TLR2/TLR1 heterodimers to directly respond toM. tuberculosisproducts.M. tuberculosislipoproteins induced NF-κ...
Mtb regulates many aspects of the host immune response, including CD4+ T lymphocyte responses tha... more Mtb regulates many aspects of the host immune response, including CD4+ T lymphocyte responses that are essential for protective immunity to Mtb, and Mtb effects on the immune system are paradoxical, having the capacity to inhibit (immune evasion) and to activate (adjuvant effect) immune cells. Mtb regulates CD4+ T cells indirectly (e.g., by manipulation of APC function) and directly, via integrins and TLRs expressed on T cells. We now report that previously uncharacterized Mtb protein Rv2468c/MT2543 can directly regulate human CD4+ T cell activation by delivering costimulatory signals. When combined with TCR stimulation (e.g., anti-CD3), Rv2468c functioned as a direct costimulator for CD4+ T cells, inducing IFN-γ secretion and T cell proliferation. Studies with blocking antibodies and soluble RGD motifs demonstrated that Rv2468c engaged integrin VLA-5 (α5β1) on CD4+ T cells through its FN-like RGD motif. Costimulation by Rv2468c induced phosphorylation of FAKs and Pyk2. These result...
Knockout of lprG results in decreased virulence of Mycobacterium tuberculosis (Mtb) in mice. Mtb ... more Knockout of lprG results in decreased virulence of Mycobacterium tuberculosis (Mtb) in mice. Mtb lipoprotein LprG has TLR2 agonist activity, thought to be dependent on its N-terminal triacylation. Surprisingly, here we find that non-acylated LprG retains TLR2 activity. Moreover, we show LprG association with triacylated glycolipid TLR2 agonists lipoarabinomannan, lipomannan and phosphatidylinositol mannosides (which share core structures). Binding of triacylated species was specific to LprG (not LprA) and increased LprG TLR2 agonist activity; conversely, association of glycolipids with LprG enhanced their recognition by TLR2. The crystal structure of LprG in complex with phosphatidylinositol mannoside revealed a hydrophobic pocket that accommodates the three alkyl chains of the ligand. In conclusion, we demonstrate a glycolipid binding function of LprG that enhances recognition of triacylated Mtb glycolipids by TLR2 and may affect glycolipid assembly or transport for bacterial cell ...
Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infec... more Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infect one-third of the world’s population. Control of M. tuberculosis requires T cells and macrophages. T-cell function is modulated by the cytokine environment, which in mycobacterial infection is a balance of proinflammatory (interleukin-1 [IL-1], IL-6, IL-8, IL-12, and tumor necrosis factor alpha) and inhibitory (IL-10 and transforming growth factor b [TGF-b]) cytokines. IL-10 and TGF-b are produced by M. tuberculosis-infected macrophages. The effect of IL-10 and TGF-b on M. tuberculosis-reactive human CD4 1 and gd T cells, the two major human T-cell subsets activated by M. tuberculosis, was investigated. Both IL-10 and TGF-b inhibited proliferation and gamma interferon production by CD4 1 and gd T cells. IL-10 was a more potent inhibitor than TGF-b for both T-cell subsets. Combinations of IL-10 and TGF-b did not result in additive or synergistic inhibition. IL-10 inhibited gd and CD4 1 T...
The impact of bone cell activation on bacterially-induced osteolysis remains elusive. Here, we sh... more The impact of bone cell activation on bacterially-induced osteolysis remains elusive. Here, we show that matrix-embedded osteocytes stimulated with bacterial pathogen-associated molecular patterns (PAMPs) directly drive bone resorption through an MYD88-regulated signaling pathway. Mice lacking MYD88, primarily in osteocytes, protect against osteolysis caused by calvarial injections of bacterial PAMPs and resist alveolar bone resorption induced by oral Porphyromonas gingivalis (Pg) infection. In contrast, mice with targeted MYD88 restoration in osteocytes exhibit osteolysis with inflammatory cell infiltration. In vitro, bacterial PAMPs induce significantly higher expression of the cytokine RANKL in osteocytes than osteoblasts. Mechanistically, activation of the osteocyte MYD88 pathway up-regulates RANKL by increasing binding of the transcription factors CREB and STAT3 to Rankl enhancers and by suppressing K48-ubiquitination of CREB/CREB binding protein and STAT3. Systemic administrat...
We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on hu... more We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on human CD4+ T cells and up-regulate T-cell receptor (TCR) triggered-Th1 responses in vitro and in vivo. To better understand the role of T-cell expressed TLR2 on CD4+ T cell differentiation and function, we conducted a gene expression analysis of naïve CD4+ T-cells stimulated in the presence or absence of TLR2 co-stimulation. Unexpectedly, naïve CD4+ T-cells co-stimulated via TLR2 show a significant up-regulation of IL-9 mRNA compared to cells co-stimulated via CD28. To further evaluate the impact of T-cell expressed TLR2 on TH9 differentiation, naïve CD4+ T cells were polyclonally stimulated under TH9 polarizing conditions with or without a TLR2 agonist. Upregulation of TH9 differentiation, evidenced by increases in both percent of IL-9 secreting cells and IL-9 in culture supernatants, was observed in cells differentiated in the presence of TLR2 agonist. Also, engagement of T-cell TLR2 up-...
Tuberculosis (TB) is the leading cause of mortality among those infected with human immunodeficie... more Tuberculosis (TB) is the leading cause of mortality among those infected with human immunodeficiency virus (HIV-1) worldwide. HIV-1 load and heterogeneity are increased both locally and systemically in active TB. Mycobacterium tuberculosis (MTB) infection supports HIV-1 replication through dysregulation of host cytokines, chemokines, and their receptors. However the possibility that mycobacterial molecules released from MTB infected macrophages directly interact with CD4+ T cells triggering HIV-1 replication has not been fully explored. We studied the direct effect of different MTB molecules on HIV-1 replication (R5-tropic strain Bal) in anti-CD3- stimulated CD4 T cells from healthy donors in an antigen+ presenting cell (APC)-free system. PIM, a major glycolipid of the mycobacterial cell wall, induced significant increases in the6 percent of HIV-1 infected T cells and the viral production in culture supernatants. In spite of structural relatedness, none of the other three major MTB ...
Although a role for TLR2 on T cells has been indicated in prior studies, in vivo stimulation of T... more Although a role for TLR2 on T cells has been indicated in prior studies, in vivo stimulation of TLR2 on T cells by Mtb and its impact on Mtb infection has not been tested. Furthermore, it is not known if the enhanced susceptibility to Mtb of Tlr2 gene knockout (ko) mice is due to its role in macrophages, on T cells or both. To address TLR2 on T cells, we generated Tlr2fl/flxCd4cre/cre mice, which lack expression of TLR2 on both CD4 and CD8 T cells, to study the in vivo role of TLR2 on T cells after aerosol infection with virulent Mtb. Deletion of TLR2 in CD4+ and CD8+ T cells reduces their ability to be co-stimulated by TLR2 ligands for cytokine production. These include both pro-(IFN-γ, TNF-α) and anti-inflammatory cytokines (IL-10). Deletion of TLR2 in T cells did not affect early control but did result in decreased late control of Mtb in the lungs of infected mice. This suggests that T cell co-stimulation by mycobacterial TLR2 ligands in vivo is important for control of infection...
Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust adapti... more Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust adaptive CD4+ T-cell responses. We have previously shown that M. tuberculosis can indirectly inhibit CD4+ T cells by suppressing the major histocompatibility complex class II antigen-presenting cell function of macrophages. This study was undertaken to determine if M. tuberculosis could directly inhibit CD4+ T-cell activation. Murine CD4+ T cells were purified from spleens by negative immunoaffinity selection followed by flow sorting. Purified CD4+ T cells were activated for 16 to 48 h with CD3 and CD28 monoclonal antibodies in the presence or absence of M. tuberculosis and its subcellular fractions. CD4+ T-cell activation was measured by interleukin 2 production, proliferation, and expression of activation markers, all of which were decreased in the presence of M. tuberculosis. Fractionation identified that M. tuberculosis cell wall glycolipids, specifically, phosphatidylinositol mannoside an...
Mycobacterium tuberculosis resides in phagosomes inside macrophages. In this study, we analyzed t... more Mycobacterium tuberculosis resides in phagosomes inside macrophages. In this study, we analyzed the kinetics and location of M. tuberculosis peptide-major histocompatibility complex class II (MHC-II) complexes in M. tuberculosis-infected human macrophages. M. tuberculosis peptide-MHC-II complexes were detected with polyclonal autologous M. tuberculosis-specific CD4+ T cells or F9A6 T hybridoma cells specific for M. tuberculosis antigen (Ag) 85B (96-111). Macrophages processed heat-killed M. tuberculosis more rapidly and efficiently than live M. tuberculosis. To determine where M. tuberculosis peptide-MHC-II complexes were formed intracellularly, macrophages incubated with heat-killed M. tuberculosis were homogenized, and subcellular compartments were separated on Percoll density gradients analyzed with T cells. In THP-1 cells, M. tuberculosis Ag 85B (96- 111)-DR1 complexes appeared initially in phagosomes, followed by MHC class II compartment (MIIC) and the plasma membrane fractions...
Mycobacterium tuberculosis survives in macrophages in the face of acquired CD4+ T-cell immunity, ... more Mycobacterium tuberculosis survives in macrophages in the face of acquired CD4+ T-cell immunity, which controls but does not eliminate the organism. Gamma interferon (IFN-γ) has a central role in host defenses against M. tuberculosis by activating macrophages and regulating major histocompatibility complex class II (MHC-II) antigen (Ag) processing. M. tuberculosis interferes with IFN-γ receptor (IFN-γR) signaling in macrophages, but the molecules responsible for this inhibition are poorly defined. This study determined that the 19-kDa lipoprotein from M. tuberculosis inhibits IFN-γ-regulated HLA-DR protein and mRNA expression in human macrophages. Inhibition of HLA-DR expression was associated with decreased processing and presentation of soluble protein Ags and M. tuberculosis bacilli to MHC-II-restricted T cells. Inhibition of HLA-DR required prolonged exposure to 19-kDa lipoprotein and was blocked with a monoclonal antibody specific for Toll-like receptor 2 (TLR-2). The 19-kDa li...
Vγ9Vδ2+ T cells (γδ T cells) are activated by Mycobacterium tuberculosis and recognize mycobacter... more Vγ9Vδ2+ T cells (γδ T cells) are activated by Mycobacterium tuberculosis and recognize mycobacterial nonpeptide phosphoantigens. The role of antigen-presenting cells in the processing and presentation of phosphoantigens to Vγ9Vδ2+ T cells is not understood. We analyzed the role of macrophages for activation of γδ T cells by a new synthetic phosphoantigen bromohydrin pyrophosphate (BrHPP) and M. tuberculosis. Macrophages greatly increased γδ T-cell activation by both BrHPP and M. tuberculosis. Fixation of macrophages before infection demonstrated that uptake of M. tuberculosis was required for presentation to γδ T cells. Antigens of M. tuberculosis remained stably associated with macrophage surface and were not removed by paraformaldehyde fixation or washing. Macrophages processed M. tuberculosis for γδ T cells through a brefeldin A-insensitive pathway, suggesting that transport through the endoplasmic reticulum and Golgi complex of a putative presenting molecule is not important in ...
ABSTRACTThe success ofMycobacterium tuberculosisas a pathogen relies on its ability to regulate t... more ABSTRACTThe success ofMycobacterium tuberculosisas a pathogen relies on its ability to regulate the host immune response.M. tuberculosiscan manipulate adaptive T cell responses indirectly by modulating antigen-presenting cell (APC) function or by directly interacting with T cells. Little is known about the role ofM. tuberculosismolecules in direct regulation of T cell function. Using a biochemical approach, we identified lipoproteins LprG and LpqH as major molecules inM. tuberculosislysate responsible for costimulation of primary human CD4+T cells. In the absence of APCs, activation of memory CD4+T cells with LprG or LpqH in combination with anti-CD3 antibody induces Th1 cytokine secretion and cellular proliferation. Lipoprotein-induced T cell costimulation was inhibited by blocking antibodies to Toll-like receptor 2 (TLR2) and TLR1, indicating that human CD4+T cells can use TLR2/TLR1 heterodimers to directly respond toM. tuberculosisproducts.M. tuberculosislipoproteins induced NF-κ...
Mtb regulates many aspects of the host immune response, including CD4+ T lymphocyte responses tha... more Mtb regulates many aspects of the host immune response, including CD4+ T lymphocyte responses that are essential for protective immunity to Mtb, and Mtb effects on the immune system are paradoxical, having the capacity to inhibit (immune evasion) and to activate (adjuvant effect) immune cells. Mtb regulates CD4+ T cells indirectly (e.g., by manipulation of APC function) and directly, via integrins and TLRs expressed on T cells. We now report that previously uncharacterized Mtb protein Rv2468c/MT2543 can directly regulate human CD4+ T cell activation by delivering costimulatory signals. When combined with TCR stimulation (e.g., anti-CD3), Rv2468c functioned as a direct costimulator for CD4+ T cells, inducing IFN-γ secretion and T cell proliferation. Studies with blocking antibodies and soluble RGD motifs demonstrated that Rv2468c engaged integrin VLA-5 (α5β1) on CD4+ T cells through its FN-like RGD motif. Costimulation by Rv2468c induced phosphorylation of FAKs and Pyk2. These result...
Knockout of lprG results in decreased virulence of Mycobacterium tuberculosis (Mtb) in mice. Mtb ... more Knockout of lprG results in decreased virulence of Mycobacterium tuberculosis (Mtb) in mice. Mtb lipoprotein LprG has TLR2 agonist activity, thought to be dependent on its N-terminal triacylation. Surprisingly, here we find that non-acylated LprG retains TLR2 activity. Moreover, we show LprG association with triacylated glycolipid TLR2 agonists lipoarabinomannan, lipomannan and phosphatidylinositol mannosides (which share core structures). Binding of triacylated species was specific to LprG (not LprA) and increased LprG TLR2 agonist activity; conversely, association of glycolipids with LprG enhanced their recognition by TLR2. The crystal structure of LprG in complex with phosphatidylinositol mannoside revealed a hydrophobic pocket that accommodates the three alkyl chains of the ligand. In conclusion, we demonstrate a glycolipid binding function of LprG that enhances recognition of triacylated Mtb glycolipids by TLR2 and may affect glycolipid assembly or transport for bacterial cell ...
Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infec... more Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infect one-third of the world’s population. Control of M. tuberculosis requires T cells and macrophages. T-cell function is modulated by the cytokine environment, which in mycobacterial infection is a balance of proinflammatory (interleukin-1 [IL-1], IL-6, IL-8, IL-12, and tumor necrosis factor alpha) and inhibitory (IL-10 and transforming growth factor b [TGF-b]) cytokines. IL-10 and TGF-b are produced by M. tuberculosis-infected macrophages. The effect of IL-10 and TGF-b on M. tuberculosis-reactive human CD4 1 and gd T cells, the two major human T-cell subsets activated by M. tuberculosis, was investigated. Both IL-10 and TGF-b inhibited proliferation and gamma interferon production by CD4 1 and gd T cells. IL-10 was a more potent inhibitor than TGF-b for both T-cell subsets. Combinations of IL-10 and TGF-b did not result in additive or synergistic inhibition. IL-10 inhibited gd and CD4 1 T...
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Papers by Roxana Rojas