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Article ; Online: Heterologous CD8 T cell immune response to HSV induced by toll like receptor ligands.

Nandakumar, Subhadra / Kumaraguru, Uday

2010 Volume 261, Issue 2, Page(s) 114–121

Abstract: A memory response is established following primary antigen exposure that stays more or less constant. It appears to adopt a set-point in magnitude but upon re-exposure the response is quicker and better and there is an upward shift in memory frequency ... ...

Abstract	A memory response is established following primary antigen exposure that stays more or less constant. It appears to adopt a set-point in magnitude but upon re-exposure the response is quicker and better and there is an upward shift in memory frequency that varies with individuals based on the exposure pattern to other microbes or its components. Our investigations were designed to test such differences of non-specific stimulation by PAMPs in lowering the threshold of activation. Neonatal mice were pre-exposed to TLR-ligands intermittently and later analyzed for its resilience to challenge with virus during adult-life. Secondly, adult mice with pre-existing memory to virus were exposed to various TLR-ligands and analyzed for their quality of memory response. The TLR-ligands exposed animals were better responders to a new agent exposure compared to the animals kept in sterile surroundings. Moreover, immune memory recall and the viral specific CD8(+) T cells response with TLR-ligands were comparable to the recall response with the cognate antigen. The results provide insights into the role of hyper-sanitized environment versus PAMPs mediated signaling in adaptive immunity and long-term immune memory.
MeSH term(s)	Adaptive Immunity/immunology ; Adult ; Animals ; Animals, Newborn ; CD8-Positive T-Lymphocytes/immunology ; Child ; Herpesvirus 1, Human/immunology ; Humans ; Immunologic Memory/immunology ; Ligands ; Mice ; Mice, Inbred C57BL ; Signal Transduction/immunology ; Spleen/cytology ; Survival Rate ; Toll-Like Receptors/immunology
Chemical Substances	Ligands ; Toll-Like Receptors
Language	English
Publishing date	2010
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2009.11.008
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Article ; Online: T regulatory cells: an overview and intervention techniques to modulate allergy outcome.

Nandakumar, Subhadra / Miller, Christopher Wt / Kumaraguru, Uday

Clinical and molecular allergy : CMA

2009 Volume 7, Page(s) 5

Abstract: Dysregulated immune response results in inflammatory symptoms in the respiratory mucosa leading to asthma and allergy in susceptible individuals. The T helper type 2 (Th2) subsets are primarily involved in this disease process. Nevertheless, there is ... ...

Abstract	Dysregulated immune response results in inflammatory symptoms in the respiratory mucosa leading to asthma and allergy in susceptible individuals. The T helper type 2 (Th2) subsets are primarily involved in this disease process. Nevertheless, there is growing evidence in support of T cells with regulatory potential that operates in non-allergic individuals. These regulatory T cells occur naturally are called natural T regulatory cells (nTregs) and express the transcription factor Foxp3. They are selected in the thymus and move to the periphery. The CD4 Th cells in the periphery can be induced to become regulatory T cells and hence called induced or adaptive T regulatory cells. These cells can make IL-10 or TGF-b or both, by which they attain most of their suppressive activity. This review gives an overview of the regulatory T cells, their role in allergic diseases and explores possible interventionist approaches to manipulate Tregs for achieving therapeutic goals.
Language	English
Publishing date	2009-03-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2126317-6
ISSN	1476-7961 ; 1476-7961
ISSN (online)	1476-7961
ISSN	1476-7961
DOI	10.1186/1476-7961-7-5
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Article ; Online: Attrition of T-cell functions and simultaneous upregulation of inhibitory markers correspond with the waning of BCG-induced protection against tuberculosis in mice.

Nandakumar, Subhadra / Kannanganat, Sunil / Posey, James E / Amara, Rama Rao / Sable, Suraj B

PloS one

2014 Volume 9, Issue 11, Page(s) e113951

Abstract: Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live attenuated vaccine. However, the correlates of protection and waning of its immunity against tuberculosis is poorly understood. In this study, we correlated the longitudinal ... ...

Abstract	Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live attenuated vaccine. However, the correlates of protection and waning of its immunity against tuberculosis is poorly understood. In this study, we correlated the longitudinal changes in the magnitude and functional quality of CD4(+) and CD8(+) T-cell response over a period of two years after mucosal or parenteral BCG vaccination with the strength of protection against Mycobacterium tuberculosis in mice. The BCG vaccination-induced CD4(+) and CD8(+) T cells exhibited comparable response kinetics but distinct functional attributes in-terms of IFN-γ, IL-2 and TNF-α co-production and CD62L memory marker expression. Despite a near life-long BCG persistence and the induction of enduring CD4(+) T-cell responses characterized by IFN-γ and/or TNF-α production with comparable protection, the protective efficacy waned regardless of the route of vaccination. The progressive decline in the multifactorial functional abilities of CD4(+) and CD8(+) T cells in-terms of type-1 cytokine production, proliferation and cytolytic potential corresponded with the waning of protection against M. tuberculosis infection. In addition, simultaneous increase in the dysfunctional and terminally-differentiated T cells expressing CTLA-4, KLRG-1 and IL-10 during the contraction phase of BCG-induced response coincided with the loss of protection. Our results question the empirical development of BCG-booster vaccines and emphasize the pursuit of strategies that maintain superior T-cell functional capacity. Furthermore, our results underscore the importance of understanding the comprehensive functional dynamics of antigen-specific T-cell responses in addition to cytokine polyfunctionality in BCG-vaccinated hosts while optimizing novel vaccination strategies against tuberculosis.
MeSH term(s)	Animals ; BCG Vaccine/administration & dosage ; BCG Vaccine/immunology ; CD4-Positive T-Lymphocytes/diagnostic imaging ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; CTLA-4 Antigen/immunology ; CTLA-4 Antigen/metabolism ; Cells, Cultured ; Cytotoxicity, Immunologic/immunology ; Enzyme-Linked Immunospot Assay ; Female ; Flow Cytometry ; Host-Pathogen Interactions/immunology ; Interferon-gamma/immunology ; Interferon-gamma/metabolism ; Interleukin-10/immunology ; Interleukin-10/metabolism ; Interleukin-2/immunology ; Interleukin-2/metabolism ; L-Selectin/immunology ; L-Selectin/metabolism ; Lectins, C-Type/immunology ; Lectins, C-Type/metabolism ; Mice, Inbred BALB C ; Mycobacterium tuberculosis/immunology ; Mycobacterium tuberculosis/physiology ; Radiography ; Time Factors ; Trans-Activators/immunology ; Trans-Activators/metabolism ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Tuberculosis/prevention & control ; Tumor Necrosis Factor-alpha/immunology ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	BCG Vaccine ; CTLA-4 Antigen ; Interleukin-2 ; KLRG1 protein, human ; Lectins, C-Type ; Trans-Activators ; Tumor Necrosis Factor-alpha ; L-Selectin (126880-86-2) ; Interleukin-10 (130068-27-8) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0113951
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Article ; Online: Attrition of T-cell functions and simultaneous upregulation of inhibitory markers correspond with the waning of BCG-induced protection against tuberculosis in mice.

Subhadra Nandakumar / Sunil Kannanganat / James E Posey / Rama Rao Amara / Suraj B Sable

PLoS ONE, Vol 9, Iss 11, p e

2014 Volume 113951

Abstract	Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live attenuated vaccine. However, the correlates of protection and waning of its immunity against tuberculosis is poorly understood. In this study, we correlated the longitudinal changes in the magnitude and functional quality of CD4(+) and CD8(+) T-cell response over a period of two years after mucosal or parenteral BCG vaccination with the strength of protection against Mycobacterium tuberculosis in mice. The BCG vaccination-induced CD4(+) and CD8(+) T cells exhibited comparable response kinetics but distinct functional attributes in-terms of IFN-γ, IL-2 and TNF-α co-production and CD62L memory marker expression. Despite a near life-long BCG persistence and the induction of enduring CD4(+) T-cell responses characterized by IFN-γ and/or TNF-α production with comparable protection, the protective efficacy waned regardless of the route of vaccination. The progressive decline in the multifactorial functional abilities of CD4(+) and CD8(+) T cells in-terms of type-1 cytokine production, proliferation and cytolytic potential corresponded with the waning of protection against M. tuberculosis infection. In addition, simultaneous increase in the dysfunctional and terminally-differentiated T cells expressing CTLA-4, KLRG-1 and IL-10 during the contraction phase of BCG-induced response coincided with the loss of protection. Our results question the empirical development of BCG-booster vaccines and emphasize the pursuit of strategies that maintain superior T-cell functional capacity. Furthermore, our results underscore the importance of understanding the comprehensive functional dynamics of antigen-specific T-cell responses in addition to cytokine polyfunctionality in BCG-vaccinated hosts while optimizing novel vaccination strategies against tuberculosis.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: T regulatory cells

Kumaraguru Uday / Miller Christopher WT / Nandakumar Subhadra

Clinical and Molecular Allergy, Vol 7, Iss 1, p

an overview and intervention techniques to modulate allergy outcome

2009 Volume 5

Abstract: Abstract Dysregulated immune response results in inflammatory symptoms in the respiratory mucosa leading to asthma and allergy in susceptible individuals. The T helper type 2 (Th2) subsets are primarily involved in this disease process. Nevertheless, ... ...

Abstract	Abstract Dysregulated immune response results in inflammatory symptoms in the respiratory mucosa leading to asthma and allergy in susceptible individuals. The T helper type 2 (Th2) subsets are primarily involved in this disease process. Nevertheless, there is growing evidence in support of T cells with regulatory potential that operates in non-allergic individuals. These regulatory T cells occur naturally are called natural T regulatory cells (nTregs) and express the transcription factor Foxp3. They are selected in the thymus and move to the periphery. The CD4 Th cells in the periphery can be induced to become regulatory T cells and hence called induced or adaptive T regulatory cells. These cells can make IL-10 or TGF-b or both, by which they attain most of their suppressive activity. This review gives an overview of the regulatory T cells, their role in allergic diseases and explores possible interventionist approaches to manipulate Tregs for achieving therapeutic goals.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Allergy and Immunology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	610
Language	English
Publishing date	2009-03-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Persistence of anti-HBs titers after two different doses of Genevac B, a recombinant hepatitis B vaccine, in healthy adolescents.

Velu, Vijayakumar / Nandakumar, Subhadra / Shanmugam, Saravanan / Thyagarajan, Sadras Panchatcharam

Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology

2007 Volume 26, Issue 1, Page(s) 48

MeSH term(s)	Adolescent ; Adult ; Child ; Female ; Hepatitis B Antibodies/biosynthesis ; Hepatitis B Surface Antigens/immunology ; Hepatitis B Vaccines/administration & dosage ; Hepatitis B Vaccines/immunology ; Humans ; Male
Chemical Substances	Hepatitis B Antibodies ; Hepatitis B Surface Antigens ; Hepatitis B Vaccines
Language	English
Publishing date	2007-03-19
Publishing country	India
Document type	Comparative Study ; Letter ; Randomized Controlled Trial
ZDB-ID	632595-6
ISSN	0254-8860
ISSN	0254-8860
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Article: The effect of methanolic extract of Tamarindus indica Linn. on the growth of clinical isolates of Burkholderia pseudomallei.

Muthu, Shankar Esaki / Nandakumar, Subhadra / Rao, Usha Anand

The Indian journal of medical research

2005 Volume 122, Issue 6, Page(s) 525–528

Abstract: Burkholderia pseudomallei (Pseudomonas pseudomallei) causes melioidosis, a life-threatening infection common among paddy cultivators in Southeast Asian countries. No plant materials have been investigated for its activity against B. pseudomallei. ... ...

Abstract	Burkholderia pseudomallei (Pseudomonas pseudomallei) causes melioidosis, a life-threatening infection common among paddy cultivators in Southeast Asian countries. No plant materials have been investigated for its activity against B. pseudomallei. Therefore, a preliminary study was carried out using disc diffusion and minimum inhibitory concentration (MIC) methods to evaluate the anti-B. pseudomallei activity of five Indian medicinal plants documented to have been used for several ailments in the ancient Indian scriptures. The leaf extracts of Tamarindus indica, Lawsonia inermis, and Hibiscus rosa-sinensis, the rhizome extracts of Curcuma longa and the seeds of Vigna radiata were prepared using methanol as solvent. The disc diffusion and MIC methods were used to assess the anti-B. pseudomallei activity of the plants tested. Only methanol leaf extracts of Tamarindus indica exhibited anti-B. pseudomallei activity starting from disc concentrations of 150 mug by the disc diffusion method. The other plants failed to show any zone of inhibition. MIC assay revealed that the MIC and minimum bactericidal concentration (MBC) for B. pseudomallei were 125 mug/ml. Our preliminary finding showed that methanolic extracts of Tamarindus indica has anti-B. pseudomallei inhibitory potentials under in vitro conditions. Extensive animal studies may be required before investigating the role of Tamarindus indica for treating melioidosis.
MeSH term(s)	Anti-Bacterial Agents/isolation & purification ; Anti-Bacterial Agents/pharmacology ; Burkholderia pseudomallei/drug effects ; Burkholderia pseudomallei/growth & development ; Burkholderia pseudomallei/isolation & purification ; Humans ; In Vitro Techniques ; Melioidosis/drug therapy ; Phytotherapy ; Plant Extracts/pharmacology ; Tamarindus
Chemical Substances	Anti-Bacterial Agents ; Plant Extracts
Language	English
Publishing date	2005-12
Publishing country	India
Document type	Journal Article
ZDB-ID	390883-5
ISSN	0971-5916 ; 0019-5340
ISSN	0971-5916 ; 0019-5340
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Article ; Online: Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis.

Nandakumar, Subhadra / Kannanganat, Sunil / Dobos, Karen M / Lucas, Megan / Spencer, John S / Amara, Rama Rao / Plikaytis, Bonnie B / Posey, James E / Sable, Suraj B

Scientific reports

2016 Volume 6, Page(s) 25837

Abstract: Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell ... ...

Abstract	Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32-52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime-Apa-subunit-boost strategy compared to Apa-subunit-prime-BCG-boost approach. However, parenteral BCG-prime-Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime-boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime-boost regimens against tuberculosis in humans.
MeSH term(s)	Adhesins, Bacterial/immunology ; Adjuvants, Immunologic/pharmacology ; Animals ; Antibody Formation/drug effects ; BCG Vaccine/immunology ; Cytokines/metabolism ; Female ; Immunity/drug effects ; Immunity, Mucosal/drug effects ; Immunization, Secondary ; Immunoglobulin G/blood ; Kinetics ; Mice, Inbred BALB C ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/immunology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Vaccines, Subunit/immunology
Chemical Substances	Adhesins, Bacterial ; Adjuvants, Immunologic ; BCG Vaccine ; Cytokines ; Immunoglobulin G ; Vaccines, Subunit
Language	English
Publishing date	2016-05-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep25837
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Article ; Online: IL-21 and IL-15 cytokine DNA augments HSV specific effector and memory CD8+ T cell response.

Rodrigues, Luiz / Nandakumar, Subhadra / Bonorino, Cristina / Rouse, Barry T / Kumaraguru, Uday

Molecular immunology

2009 Volume 46, Issue 7, Page(s) 1494–1504

Abstract: The recurrence of lesions and transmission of Herpes simplex virus is dependent on the number and function of viral specific CD8(+) T cells, especially the memory T cells. The generation, turnover and set point of this cell population is maintained by ... ...

Abstract	The recurrence of lesions and transmission of Herpes simplex virus is dependent on the number and function of viral specific CD8(+) T cells, especially the memory T cells. The generation, turnover and set point of this cell population is maintained by different factors like exposure to antigen, cytokines and co-stimulatory molecules. However, the contribution of these factors in the generation and maintenance of the memory CD8(+) T cell population is still controversial, since it is not clear if homeostatic proliferation driven by cytokines can overcome T cell receptor (TCR) signaling. Since, interleukin 15 (IL-15) and interleukin 21 (IL-21) are cytokines implicated in homeostatic control of CD8(+) T cell pool, we constructed and used expression plasmids coding for IL-15 (pIL-15) and IL-21 (pIL-21) to expand HSV specific CD8(+) T cells in an animal model. Our results showed that the IL-21 increased the frequency of CD8(+) T cells in the absence of antigen, although the magnitude of this response was dependent on TCR signaling. Both pIL-15 and pIL-21 boosted the numbers of antigen specific CD8(+) IFNgamma producing cells in the primary response. In the memory phase, numbers of CD8(+) CD44(high) as well as CD8(+) T cells producing IFN-gamma and TNF-alpha were increased when pIL-15 and pIL-21 were used alone or in combination, compared to vector treatment only, and association of antigen further increased the proliferative response. Our data suggest that genetic treatment with pIL-15 and pIL-21 in the presence or absence of cognate antigen can contribute to immune-enhancement against HSV.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Cercopithecus aethiops ; DNA/immunology ; DNA/physiology ; Female ; Genetic Therapy ; Humans ; Immunologic Memory/physiology ; Immunotherapy/methods ; Interleukin-15/genetics ; Interleukin-15/immunology ; Interleukins/genetics ; Interleukins/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Rats ; Simplexvirus/immunology ; T-Cell Antigen Receptor Specificity ; T-Lymphocytes/immunology ; Vero Cells
Chemical Substances	Interleukin-15 ; Interleukins ; interleukin-21 ; DNA (9007-49-2)
Language	English
Publishing date	2009-04
Publishing country	England
Document type	Evaluation Studies ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2008.12.033
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Article ; Online: Natural killer cells as novel helpers in anti-herpes simplex virus immune response.

Nandakumar, Subhadra / Woolard, Stacie N / Yuan, Dorothy / Rouse, Barry T / Kumaraguru, Uday

Journal of virology

2008 Volume 82, Issue 21, Page(s) 10820–10831

Abstract: Innate defenses help to eliminate infection, but some of them also play a major role in shaping the magnitude and efficacy of the adaptive immune response. With regard to influencing subsequent adaptive immunity, NK cells aided by dendritic cells may be ... ...

Abstract	Innate defenses help to eliminate infection, but some of them also play a major role in shaping the magnitude and efficacy of the adaptive immune response. With regard to influencing subsequent adaptive immunity, NK cells aided by dendritic cells may be the most relevant components of the innate reaction to herpes simplex virus (HSV) infection. We confirm that mice lacking or depleted of NK cells are susceptible to HSV-induced lesions. The quantity and quality of CD8(+) cytotoxic T lymphocytes generated in the absence of NK cells were diminished, thereby contributing to susceptibility to HSV-induced encephalitis. We demonstrate a novel helper role for NK cells, in that NK cells compensate for the loss of CD4 helper T cells and NK cell supplementation enhances the function of wild type anti-HSV CD8 T cells. In addition, NK cells were able to partially rescue the dysfunctional CD8(+) T cells generated in the absence of CD4 T helper cells, thereby performing a novel rescue function. Hence, NK cells may well be exploited for enhancing and rescuing the T-cell response in situations where the CD4 helper response is affected.
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line ; Chlorocebus aethiops ; Encephalitis, Viral/immunology ; Herpesvirus 1, Human/immunology ; Killer Cells, Natural/immunology ; Leukocyte Reduction Procedures ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes, Helper-Inducer/immunology
Language	English
Publishing date	2008-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00365-08
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