Summary Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infect... more Summary Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infectious agent and has significant implications for global health. A major hurdle in the development of effective TB vaccines and therapies is the absence of defined immune-correlates of protection. In this context, the role of regulatory T cells (Treg), which are essential for maintaining immune homeostasis, is even less understood. This review aims to address this knowledge gap by providing an overview of the emerging patterns of Treg function in TB. Increasing evidence from studies, both in animal models of infection and TB patients, points to the fact the role of Tregs in TB is dependent on disease stage. While Tregs might expand and delay the appearance of protective responses in the early stages of infection, their role in the chronic phase perhaps is to counter-regulate excessive inflammation. New data highlight that this important homeostatic role of Tregs in the chronic phase of TB ...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2018
PPE18 is a member of the PPE family. Previous studies have shown that recombinant PPE18 (rPPE18) ... more PPE18 is a member of the PPE family. Previous studies have shown that recombinant PPE18 (rPPE18) protein binds to TLR2 and triggers a signaling cascade which reduces levels of TNF-α and IL-12, and increases IL-10 in macrophages. Because TNF-α is a major mediator of the pathophysiology of sepsis and blocking inflammation is a possible line of therapy in such circumstances, we tested the efficacy of rPPE18 in reducing symptoms of sepsis in a mouse model of induced septic peritonitis. rPPE18 significantly decreased levels of serum TNF-α, IL-1β, IL-6, and IL-12 and reduced organ damage in mice injected i.p. with high doses of Peritoneal cells isolated from rPPE18-treated mice had characteristics of M2 macrophages which are protective in excessive inflammation. Additionally, rPPE18 inhibited disseminated intravascular coagulation, which can cause organ damage resulting in death. rPPE18 was able to reduce sepsis-induced mortality when given prophylactically or therapeutically. Additionall...
How do we remain healthy, for the most parts, in the midst of an environment teeming with opportu... more How do we remain healthy, for the most parts, in the midst of an environment teeming with opportunistic and infectious microbes, potential carcinogens and allergens? The fact is that our immune system, by and large, does a fine job in protecting us. It is therefore important to understand the organization of the immune network, which is broadly categorized into two groups: innate and adaptive. Cells involved in innate immunity are the first to come into contact with invading microbes, similar to the border security force, and respond rapidly but in a non-specific manner. On the other hand, the cells involved in adaptive immunity are slower to respond but act in a very specific manner. Though the primary response is slow, the secondary response is much faster and demonstrates memory. This article will focus on some important features and key players involved in the adaptive immune response. The first part deals with the humoral immune response mediated mainly by immunoglobulins produced by the B cells. The second part deals with T cells, the Major Histocompatibility Complex (MHC)encoded molecules, and Recombination Activating Genes (RAG) responsible for generating diverse B-cell receptors (BCR) and T-cell receptors (TCR). With the advent of newer and smarter infectious agents, it is important to understand the working of the immune network as more research in this area may facilitate the development of better protective strategies.
Abstract Optimal T cell function lies at the heart of an efficient adaptive response. T cell acti... more Abstract Optimal T cell function lies at the heart of an efficient adaptive response. T cell activation is a highly regulated process and it is important to ensure that acti-vation occurs in the proper context to prevent the development of harmful conditions such as autoimmunity and ...
Mycobacterium indicus pranii (MIP) is approved for use as an adjuvant (Immuvac/Cadi-05) in the tr... more Mycobacterium indicus pranii (MIP) is approved for use as an adjuvant (Immuvac/Cadi-05) in the treatment of leprosy. In addition, its efficacy is being investigated in clinical trials on patients with tuberculosis and different tumors. To evaluate and delineate the mechanisms by which autoclaved MIP enhances anti-tumor responses, the growth of solid tumors consisting of Sp2/0 (myeloma) and EL4 (thymoma) cells was studied in BALB/c and C57BL/6 mice, respectively. Treatment of mice with a single intra-dermal (i.d.) injection of MIP 3 days after Sp2/0 implantation greatly suppresses tumor growth. MIP treatment of tumor bearing mice lowers Interleukin (IL)6 but increases IL12p70 and IFNγ amounts in sera. Also, increase in CD8(+) T cell mediated lysis of specific tumor targets and production of high amounts of IL2 and IFNγ by CD4(+) T cells upon stimulation with specific tumor antigens in MIP treated mice is observed. Furthermore, MIP is also effective in reducing the growth of EL4 tumors; however, this efficacy is reduced in Ifnγ(-/-) mice. In fact, several MIP mediated anti-tumor responses are greatly abrogated in Ifnγ(-/-) mice: increase in serum Interleukin (IL)12p70 amounts, induction of IL2 and lysis of EL4 targets by splenocytes upon stimulation with specific tumor antigens. Interestingly, tumor-induced increase in serum IL12p70 and IFNγ and reduction in growth of Sp2/0 and EL4 tumors by MIP are not observed in nonobese diabetic severe combined immunodeficiency mice. Overall, our study clearly demonstrates the importance of a functional immune network, in particular endogenous CD4(+) and CD8(+) T cells and IFNγ, in mediating the anti-tumor responses by MIP.
Chronic T cell activation is a hallmark of pulmonary tuberculosis (PTB). The mechanisms underpinn... more Chronic T cell activation is a hallmark of pulmonary tuberculosis (PTB). The mechanisms underpinning this important phenomenon are however, poorly elucidated, though known to rely on control of T effector cells (Teff) by regulatory T cells (Treg). Our studies show that circulating natural Treg cells in adults with PTB preserve their suppressive potential but Teff cells from such subjects are resistant to Treg-mediated suppression. We found this to be due to expansion of an activated Teff subset identified by Human Leukocyte Antigen (HLA)-DR expression. Sensitivity to suppression was restored to control levels by depletion of this subset. Comparative transcriptome analysis of Teff cells that contain HLA-DR+ cells versus the fraction depleted of this population identified putative resistance mechanisms linked to IFNG, IL17A, IL22, PD-L1 and β-chemokines CCL3L3, CCL4 expression. Antibody blocking experiments confirmed HLA-DR+ Teff cells, but not the fraction depleted of HLA-DR+ effecto...
Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a well-studied T cell costimulatory receptor that is ... more Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a well-studied T cell costimulatory receptor that is known to inhibit T cell activation. In this study, the relationship between strength of the first signal and costimulatory interactions on primary mouse CD4(+) T cells was investigated. CTLA4-CD80/CD86 interactions differentially modulate T cell cycling based on the mode of CD3 signal: Activation with plate-bound (pb) anti-CD3 generates a strong signal compared with a weak signal with soluble (sol) anti-CD3, resulting in approximately sevenfold higher amounts of interleukin (IL)-2 and an increase in cell cycling. Activation of T cells with sol anti-CD3 (weak signal) together with CTLA4-CD80/CD86 blockade lowers IL-2 production and cell cycling, demonstrating an enhancing role for these interactions. Conversely, blockade of CTLA4-CD80/CD86 interactions on T cells activated with pb anti-CD3 (strong signal) increases proliferation, which is consistent with CTLA4 as a negative regulator. Als...
Our immune system, by and large, does a fine job in protecting us from opportunistic and infectio... more Our immune system, by and large, does a fine job in protecting us from opportunistic and infectious microbes, potential carcinogens and allergens. It is therefore crucial to understand the organization of the immune network. This article focuses on some important features and key players involved in adaptive immune response. The first part of the article dealt with the humoral immune response mediated mainly by immunoglobulins produced by the B cells. The second part deals with T cells, the Major Histocompatibility Complex (MHC)-encoded molecules, and Recombination Activating Genes (RAG) responsible for generating diverse B-cell receptors (BCR) and T-cell receptors (TCR). With the advent of newer and smarter infectious agents, it is important to understand the working of the immune network as more research in this area may facilitate the development of better protective strategies.
How do we remain healthy, for the most parts, in the midst of an environment teeming with opportu... more How do we remain healthy, for the most parts, in the midst of an environment teeming with opportunistic and infectious microbes, potential carcinogens and allergens? The fact is that our immune system, by and large, does a fine job in protecting us. It is therefore important to understand the organization of the immune network, which is broadly categorized into two groups: innate and adaptive. Cells involved in innate immunity are the first to come into contact with invading microbes, similar to the border security force, and respond rapidly but in a non-specific manner. On the other hand, the cells involved in adaptive immunity are slower to respond but act in a very specific manner. Though the primary response is slow, the secondary response is much faster and demonstrates memory. This article will focus on some important features and key players involved in the adaptive immune response. The first part deals with the humoral immune response mediated mainly by immunoglobulins produced by the B cells. The second part deals with T cells, the Major Histocompatibility Complex (MHC)-encoded molecules, and Recombination Activating Genes (RAG) responsible for generating diverse B-cell receptors (BCR) and T-cell receptors (TCR). With the advent of newer and smarter infectious agents, it is important to understand the working of the immune network as more research in this area may facilitate the development of better protective strategies.
The identification of small molecules that affect T cell activation is an important area of resea... more The identification of small molecules that affect T cell activation is an important area of research. Three molecules that regulate plant growth and differentiation, but not their structurally similar analogs, were identified to enhance primary mouse CD4+ T cell activation in conjunction with soluble anti-CD3 stimulation: Indoleacetic acid (natural plant auxin), 1-Napthaleneacetic acid (synthetic plant auxin) and 2,4-Dichlorophenoxyacetic acid (synthetic plant auxin and herbicide). These effects are distinct in comparison to Curcumin, the well known phenolic immunomodulator, which lowers T cell activation. An investigation into the mechanisms of action of the three plant growth regulators revealed a rapid induction of reactive oxygen species (ROS), mainly comprising H2O2. In addition, these three molecules synergize with soluble anti-CD3 signaling to enhance intracellular Ca2+ concentrations [Ca2+]i, leading to greater T cell activation, e.g. induction of CD25 and IL-2. Enhanced production of TNFα and IFNγ by CD4+ T cells is also observed upon plant growth regulator treatment with soluble anti-CD3. Interestingly, maximal IL-2 production and CD4+ T cell cycle progression are observed upon activation with soluble anti-CD3 and phorbol 12-myristate 13-acetate (PMA), a phorbol ester. Additionally, stimulation with PMA and Ionomcyin (a Ca2+ ionophore), which activates T cells by circumventing the TCR, and plant growth regulators also demonstrated the role of the strength of signal (SOS): T cell cycle progression is enhanced with gentle activation conditions but decreased with strong activation conditions. This study demonstrates the direct effects of three plant growth regulators on CD4+ T cell activation and cycling.► Plant growth regulators (NAA, 2,4D & IAA) enhance CD4+ T cell activation by anti-CD3. ► NAA, 2,4D & IAA increase intracellular ROS and Ca2+ upon anti-CD3 stimulation. ► The rapid induction of ROS leads to rise in intracellular Ca2+. ► NAA, 2,4D & IAA modulate CD4+ T cell cycling depending on the strength of signal. ► NAA, 2,4D & IAA directly affect in vitro CD4+ T cell activation and cycling.
Summary Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infect... more Summary Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infectious agent and has significant implications for global health. A major hurdle in the development of effective TB vaccines and therapies is the absence of defined immune-correlates of protection. In this context, the role of regulatory T cells (Treg), which are essential for maintaining immune homeostasis, is even less understood. This review aims to address this knowledge gap by providing an overview of the emerging patterns of Treg function in TB. Increasing evidence from studies, both in animal models of infection and TB patients, points to the fact the role of Tregs in TB is dependent on disease stage. While Tregs might expand and delay the appearance of protective responses in the early stages of infection, their role in the chronic phase perhaps is to counter-regulate excessive inflammation. New data highlight that this important homeostatic role of Tregs in the chronic phase of TB ...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2018
PPE18 is a member of the PPE family. Previous studies have shown that recombinant PPE18 (rPPE18) ... more PPE18 is a member of the PPE family. Previous studies have shown that recombinant PPE18 (rPPE18) protein binds to TLR2 and triggers a signaling cascade which reduces levels of TNF-α and IL-12, and increases IL-10 in macrophages. Because TNF-α is a major mediator of the pathophysiology of sepsis and blocking inflammation is a possible line of therapy in such circumstances, we tested the efficacy of rPPE18 in reducing symptoms of sepsis in a mouse model of induced septic peritonitis. rPPE18 significantly decreased levels of serum TNF-α, IL-1β, IL-6, and IL-12 and reduced organ damage in mice injected i.p. with high doses of Peritoneal cells isolated from rPPE18-treated mice had characteristics of M2 macrophages which are protective in excessive inflammation. Additionally, rPPE18 inhibited disseminated intravascular coagulation, which can cause organ damage resulting in death. rPPE18 was able to reduce sepsis-induced mortality when given prophylactically or therapeutically. Additionall...
How do we remain healthy, for the most parts, in the midst of an environment teeming with opportu... more How do we remain healthy, for the most parts, in the midst of an environment teeming with opportunistic and infectious microbes, potential carcinogens and allergens? The fact is that our immune system, by and large, does a fine job in protecting us. It is therefore important to understand the organization of the immune network, which is broadly categorized into two groups: innate and adaptive. Cells involved in innate immunity are the first to come into contact with invading microbes, similar to the border security force, and respond rapidly but in a non-specific manner. On the other hand, the cells involved in adaptive immunity are slower to respond but act in a very specific manner. Though the primary response is slow, the secondary response is much faster and demonstrates memory. This article will focus on some important features and key players involved in the adaptive immune response. The first part deals with the humoral immune response mediated mainly by immunoglobulins produced by the B cells. The second part deals with T cells, the Major Histocompatibility Complex (MHC)encoded molecules, and Recombination Activating Genes (RAG) responsible for generating diverse B-cell receptors (BCR) and T-cell receptors (TCR). With the advent of newer and smarter infectious agents, it is important to understand the working of the immune network as more research in this area may facilitate the development of better protective strategies.
Abstract Optimal T cell function lies at the heart of an efficient adaptive response. T cell acti... more Abstract Optimal T cell function lies at the heart of an efficient adaptive response. T cell activation is a highly regulated process and it is important to ensure that acti-vation occurs in the proper context to prevent the development of harmful conditions such as autoimmunity and ...
Mycobacterium indicus pranii (MIP) is approved for use as an adjuvant (Immuvac/Cadi-05) in the tr... more Mycobacterium indicus pranii (MIP) is approved for use as an adjuvant (Immuvac/Cadi-05) in the treatment of leprosy. In addition, its efficacy is being investigated in clinical trials on patients with tuberculosis and different tumors. To evaluate and delineate the mechanisms by which autoclaved MIP enhances anti-tumor responses, the growth of solid tumors consisting of Sp2/0 (myeloma) and EL4 (thymoma) cells was studied in BALB/c and C57BL/6 mice, respectively. Treatment of mice with a single intra-dermal (i.d.) injection of MIP 3 days after Sp2/0 implantation greatly suppresses tumor growth. MIP treatment of tumor bearing mice lowers Interleukin (IL)6 but increases IL12p70 and IFNγ amounts in sera. Also, increase in CD8(+) T cell mediated lysis of specific tumor targets and production of high amounts of IL2 and IFNγ by CD4(+) T cells upon stimulation with specific tumor antigens in MIP treated mice is observed. Furthermore, MIP is also effective in reducing the growth of EL4 tumors; however, this efficacy is reduced in Ifnγ(-/-) mice. In fact, several MIP mediated anti-tumor responses are greatly abrogated in Ifnγ(-/-) mice: increase in serum Interleukin (IL)12p70 amounts, induction of IL2 and lysis of EL4 targets by splenocytes upon stimulation with specific tumor antigens. Interestingly, tumor-induced increase in serum IL12p70 and IFNγ and reduction in growth of Sp2/0 and EL4 tumors by MIP are not observed in nonobese diabetic severe combined immunodeficiency mice. Overall, our study clearly demonstrates the importance of a functional immune network, in particular endogenous CD4(+) and CD8(+) T cells and IFNγ, in mediating the anti-tumor responses by MIP.
Chronic T cell activation is a hallmark of pulmonary tuberculosis (PTB). The mechanisms underpinn... more Chronic T cell activation is a hallmark of pulmonary tuberculosis (PTB). The mechanisms underpinning this important phenomenon are however, poorly elucidated, though known to rely on control of T effector cells (Teff) by regulatory T cells (Treg). Our studies show that circulating natural Treg cells in adults with PTB preserve their suppressive potential but Teff cells from such subjects are resistant to Treg-mediated suppression. We found this to be due to expansion of an activated Teff subset identified by Human Leukocyte Antigen (HLA)-DR expression. Sensitivity to suppression was restored to control levels by depletion of this subset. Comparative transcriptome analysis of Teff cells that contain HLA-DR+ cells versus the fraction depleted of this population identified putative resistance mechanisms linked to IFNG, IL17A, IL22, PD-L1 and β-chemokines CCL3L3, CCL4 expression. Antibody blocking experiments confirmed HLA-DR+ Teff cells, but not the fraction depleted of HLA-DR+ effecto...
Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a well-studied T cell costimulatory receptor that is ... more Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a well-studied T cell costimulatory receptor that is known to inhibit T cell activation. In this study, the relationship between strength of the first signal and costimulatory interactions on primary mouse CD4(+) T cells was investigated. CTLA4-CD80/CD86 interactions differentially modulate T cell cycling based on the mode of CD3 signal: Activation with plate-bound (pb) anti-CD3 generates a strong signal compared with a weak signal with soluble (sol) anti-CD3, resulting in approximately sevenfold higher amounts of interleukin (IL)-2 and an increase in cell cycling. Activation of T cells with sol anti-CD3 (weak signal) together with CTLA4-CD80/CD86 blockade lowers IL-2 production and cell cycling, demonstrating an enhancing role for these interactions. Conversely, blockade of CTLA4-CD80/CD86 interactions on T cells activated with pb anti-CD3 (strong signal) increases proliferation, which is consistent with CTLA4 as a negative regulator. Als...
Our immune system, by and large, does a fine job in protecting us from opportunistic and infectio... more Our immune system, by and large, does a fine job in protecting us from opportunistic and infectious microbes, potential carcinogens and allergens. It is therefore crucial to understand the organization of the immune network. This article focuses on some important features and key players involved in adaptive immune response. The first part of the article dealt with the humoral immune response mediated mainly by immunoglobulins produced by the B cells. The second part deals with T cells, the Major Histocompatibility Complex (MHC)-encoded molecules, and Recombination Activating Genes (RAG) responsible for generating diverse B-cell receptors (BCR) and T-cell receptors (TCR). With the advent of newer and smarter infectious agents, it is important to understand the working of the immune network as more research in this area may facilitate the development of better protective strategies.
How do we remain healthy, for the most parts, in the midst of an environment teeming with opportu... more How do we remain healthy, for the most parts, in the midst of an environment teeming with opportunistic and infectious microbes, potential carcinogens and allergens? The fact is that our immune system, by and large, does a fine job in protecting us. It is therefore important to understand the organization of the immune network, which is broadly categorized into two groups: innate and adaptive. Cells involved in innate immunity are the first to come into contact with invading microbes, similar to the border security force, and respond rapidly but in a non-specific manner. On the other hand, the cells involved in adaptive immunity are slower to respond but act in a very specific manner. Though the primary response is slow, the secondary response is much faster and demonstrates memory. This article will focus on some important features and key players involved in the adaptive immune response. The first part deals with the humoral immune response mediated mainly by immunoglobulins produced by the B cells. The second part deals with T cells, the Major Histocompatibility Complex (MHC)-encoded molecules, and Recombination Activating Genes (RAG) responsible for generating diverse B-cell receptors (BCR) and T-cell receptors (TCR). With the advent of newer and smarter infectious agents, it is important to understand the working of the immune network as more research in this area may facilitate the development of better protective strategies.
The identification of small molecules that affect T cell activation is an important area of resea... more The identification of small molecules that affect T cell activation is an important area of research. Three molecules that regulate plant growth and differentiation, but not their structurally similar analogs, were identified to enhance primary mouse CD4+ T cell activation in conjunction with soluble anti-CD3 stimulation: Indoleacetic acid (natural plant auxin), 1-Napthaleneacetic acid (synthetic plant auxin) and 2,4-Dichlorophenoxyacetic acid (synthetic plant auxin and herbicide). These effects are distinct in comparison to Curcumin, the well known phenolic immunomodulator, which lowers T cell activation. An investigation into the mechanisms of action of the three plant growth regulators revealed a rapid induction of reactive oxygen species (ROS), mainly comprising H2O2. In addition, these three molecules synergize with soluble anti-CD3 signaling to enhance intracellular Ca2+ concentrations [Ca2+]i, leading to greater T cell activation, e.g. induction of CD25 and IL-2. Enhanced production of TNFα and IFNγ by CD4+ T cells is also observed upon plant growth regulator treatment with soluble anti-CD3. Interestingly, maximal IL-2 production and CD4+ T cell cycle progression are observed upon activation with soluble anti-CD3 and phorbol 12-myristate 13-acetate (PMA), a phorbol ester. Additionally, stimulation with PMA and Ionomcyin (a Ca2+ ionophore), which activates T cells by circumventing the TCR, and plant growth regulators also demonstrated the role of the strength of signal (SOS): T cell cycle progression is enhanced with gentle activation conditions but decreased with strong activation conditions. This study demonstrates the direct effects of three plant growth regulators on CD4+ T cell activation and cycling.► Plant growth regulators (NAA, 2,4D & IAA) enhance CD4+ T cell activation by anti-CD3. ► NAA, 2,4D & IAA increase intracellular ROS and Ca2+ upon anti-CD3 stimulation. ► The rapid induction of ROS leads to rise in intracellular Ca2+. ► NAA, 2,4D & IAA modulate CD4+ T cell cycling depending on the strength of signal. ► NAA, 2,4D & IAA directly affect in vitro CD4+ T cell activation and cycling.
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