Sushama R Chaphalkar et al.

/ WJPBT, 2014, 1(1): 1114

World Journal of Pharmacy and Biotechnology 11
World Journal of Pharmacy and Biotechnology
Journal Home Page: www.pharmaresearchlibrary.com/wjpbt
Review Article
Symbiosis of toll like Receptors and Dendritic cells in vaccine
development
Amit Gupta*, Pallavi Khamkar and Sushama R Chaphalkar
Vidya Pratishthans School of Biotechnology (VSBT), Vidyanagari Baramati-413133, Pune, India.
A B S T R A C T
The activation of the adaptive immune system is generally dependent on antigen presenting cells i.e. dendritic cells and
macrophages. One of members which are already present on dendritic cells i.e. Toll-like receptor is key regulators of both
innate and adaptive immune responses. Accordingly, recent evidence from human studies and experimental animal models
studies which implicates that toll like receptors played an important role in vaccine development. However, fundamental
questions remain unanswered concerning the actual role of toll like receptors in dendritic cell. In this review, we discuss the
proposed roles of toll like receptors in dendritic cells and correlates with vaccine development.
Keywords: Toll like receptor, immune, vaccine, dendritic cells, macrophages
A R T I C L E I N F O
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
2. Dendritic cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
3. Toll like receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 13
5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Article history: Received 18 March 2014, Accepted 19 June 2014, Available Online 29 July 2014
PAPER-QR CODE
Citation: Amit Gupta, Pallavi Khamkar, Sushama R Chaphalkar. Symbiosis of toll like receptors and dendritic cells in
vaccine development. W. J. Pharm. Biotech., 2014, 1(1): 11-14
Copyright 2014 Sushama R Chaphalkar et al. This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium,
provided the original work is properly cited.
1. Introduction
The role of our immune system is to protect us against
invading pathogens and harmful agents. Generally, these
pathogens are firstly recognized by cells of the innate
immune system, i.e. Toll like receptors, complement system
etc and more challenging infections require the onset of the
*Corresponding Author
Dr. Sushama R Chaphalkar
Director, Vidya Pratishthans School of Biotechnology,
Vidyanagari Baramati-413133, Pune, India
Manuscript ID: WJPBT2040
Sushama R Chaphalkar et al. / WJPBT, 2014, 1(1): 1114
World Journal of Pharmacy and Biotechnology 11
World Journal of Pharmacy and Biotechnology
Journal Home Page: www.pharmaresearchlibrary.com/wjpbt
Review Article
Symbiosis of toll like Receptors and Dendritic cells in vaccine
development
Amit Gupta*, Pallavi Khamkar and Sushama R Chaphalkar
Vidya Pratishthans School of Biotechnology (VSBT), Vidyanagari Baramati-413133, Pune, India.
A B S T R A C T
The activation of the adaptive immune system is generally dependent on antigen presenting cells i.e. dendritic cells and
macrophages. One of members which are already present on dendritic cells i.e. Toll-like receptor is key regulators of both
innate and adaptive immune responses. Accordingly, recent evidence from human studies and experimental animal models
studies which implicates that toll like receptors played an important role in vaccine development. However, fundamental
questions remain unanswered concerning the actual role of toll like receptors in dendritic cell. In this review, we discuss the
proposed roles of toll like receptors in dendritic cells and correlates with vaccine development.
Keywords: Toll like receptor, immune, vaccine, dendritic cells, macrophages
A R T I C L E I N F O
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
2. Dendritic cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
3. Toll like receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 13
5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Article history: Received 18 March 2014, Accepted 19 June 2014, Available Online 29 July 2014
PAPER-QR CODE
Citation: Amit Gupta, Pallavi Khamkar, Sushama R Chaphalkar. Symbiosis of toll like receptors and dendritic cells in
vaccine development. W. J. Pharm. Biotech., 2014, 1(1): 11-14
Copyright 2014 Sushama R Chaphalkar et al. This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium,
provided the original work is properly cited.
1. Introduction
The role of our immune system is to protect us against
invading pathogens and harmful agents. Generally, these
pathogens are firstly recognized by cells of the innate
immune system, i.e. Toll like receptors, complement system
etc and more challenging infections require the onset of the
*Corresponding Author
Dr. Sushama R Chaphalkar
Director, Vidya Pratishthans School of Biotechnology,
Vidyanagari Baramati-413133, Pune, India
Manuscript ID: WJPBT2040
Sushama R Chaphalkar et al. / WJPBT, 2014, 1(1): 1114
World Journal of Pharmacy and Biotechnology 11
World Journal of Pharmacy and Biotechnology
Journal Home Page: www.pharmaresearchlibrary.com/wjpbt
Review Article
Symbiosis of toll like Receptors and Dendritic cells in vaccine
development
Amit Gupta*, Pallavi Khamkar and Sushama R Chaphalkar
Vidya Pratishthans School of Biotechnology (VSBT), Vidyanagari Baramati-413133, Pune, India.
A B S T R A C T
The activation of the adaptive immune system is generally dependent on antigen presenting cells i.e. dendritic cells and
macrophages. One of members which are already present on dendritic cells i.e. Toll-like receptor is key regulators of both
innate and adaptive immune responses. Accordingly, recent evidence from human studies and experimental animal models
studies which implicates that toll like receptors played an important role in vaccine development. However, fundamental
questions remain unanswered concerning the actual role of toll like receptors in dendritic cell. In this review, we discuss the
proposed roles of toll like receptors in dendritic cells and correlates with vaccine development.
Keywords: Toll like receptor, immune, vaccine, dendritic cells, macrophages
A R T I C L E I N F O
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
2. Dendritic cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
3. Toll like receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 13
5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Article history: Received 18 March 2014, Accepted 19 June 2014, Available Online 29 July 2014
PAPER-QR CODE
Citation: Amit Gupta, Pallavi Khamkar, Sushama R Chaphalkar. Symbiosis of toll like receptors and dendritic cells in
vaccine development. W. J. Pharm. Biotech., 2014, 1(1): 11-14
Copyright 2014 Sushama R Chaphalkar et al. This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium,
provided the original work is properly cited.
1. Introduction
The role of our immune system is to protect us against
invading pathogens and harmful agents. Generally, these
pathogens are firstly recognized by cells of the innate
immune system, i.e. Toll like receptors, complement system
etc and more challenging infections require the onset of the
*Corresponding Author
Dr. Sushama R Chaphalkar
Director, Vidya Pratishthans School of Biotechnology,
Vidyanagari Baramati-413133, Pune, India
Manuscript ID: WJPBT2040
Sushama R Chaphalkar et al. / WJPBT, 2014, 1(1): 1114
World Journal of Pharmacy and Biotechnology 12
adaptive immune system, which consists of T and B cells
e.g. cytotoxic T lymphocytes which kill infected cells and
helper T cells that aid B cells to differentiate into plasma
cells producing antibodies for clearance of extracellular
pathogens and also has the ability to induce memory
responses. The induction of immunological memory
provides a rapid protection against intracellular as well as
extracellular pathogens, which is the essence of
vaccination.
Vaccines represent one of the most successful strategies in
medical history. On the basis of mechanistic perspective,
vaccination only worked by manipulating the immune
response either stimulatory or suppressive through
selecting, activating or inhibiting and expanding the
memory of B and T cells. To determine the quality and
magnitude of complex type of immune response against any
vaccine antigen, suitable agonists for toll like receptors are
required for eliminating the infectious diseases. Recently,
there is ongoing effort to develop new agonist which is
safe, potent and non toxic. Significant research is being
done in this area, to develop new agonist of toll like
receptors against intracellular as well as extracellular
pathogens but also in the treatment of autoimmune diseases,
allergies and cancer. Recently, researcher has focused on
novel molecules that enhance dendritic cell function and
their ability to prime T cells. So, researchers focused on
agonists that target toll-like receptors are being used
clinically either alone or in combination with tumor
antigens and showing initial success both in terms of
enhancing immune responses and eliciting antitumor
activity.
2. Dendritic cells
Dendritic cells were first described by Ralph Steinman with
the help of his mentor Zanvil Cohn at Rockefeller
University nearly forty years ago. Steinmann was the first
person to identify the dendritic cell which is the most
powerful cell in the investigation of the T cell response and
also mention about the link between the innate and adaptive
immunity [1]. On the basis of this work, he got the Nobel
Prize in 2011 but he died just three days before the official
announcement of the Nobel Prize.
The combination of the presence and absence of various
surface markers has been used to identify dendritic cells.
These include the presence of large amounts of class II
MHC antigens and the absence of various lineage markers
such as CD3 (T cell), CD14 (monocyte), CD19 (B cell),
CD56 (natural killer cell) and CD66b (granulocyte).
Dendritic cells also express a variety of adhesion molecules
including CD11a (LFA-1), CD11c, CD50 (ICAM-2), CD54
(ICAM-1), CD58 (LFA-3), and CD102 (ICAM-3).
Dendritic cells also express costimulatory molecules
including CD80 (B7.1), and CD86 (B7.2), which are
upregulated during dendritic cells activation.
CD86 tends to be a marker of early dendritic cell
maturation (Fig. 1), while CD80 only appears in mature
dendritic cells. Two additional markers of mature dendritic
cell in humans are CD83 and CMRF-44. CD83 also stains
activated B cells and will also stain macrophages and
Monocytes. Recently, subsets of dendritic cell were
recognized based on their function in immune responses.
One of the types of dendritic cells i.e. myeloid dendritic
cells, express different TLR-2, -3, -4, and -7. After
encountering different natural ligands or pathogens for this
toll like receptors in the blood, dendritic cells become
activated and mature into antigen-presenting cells that can
secrete Th-1 or Th-2 cytokines and prime naive T cells for a
proper immune response. Another type of dendritic cell i.e.
plasmacytoid dendritic cell, only express TLR7 and TLR9
receptors and are the principle producers of interferon-alpha
after encountering invading viruses. These two types of
dendritic cells play important role on linking the innate and
adaptive immunity through their unique expression patterns
of TLRs and cytokine production.
Recently, the use of agonists by toll like receptors has
opened up new opportunities for vaccine antigen, by
synthesizing novel agonists i.e., pathogen associated
molecular pattern molecules that induce the immune
response e.g. new malaria vaccine currently being
developed [2]: thus, an antigen already studied before but
discarded as ineffective antigen but he has gained renewed
interest by being matched with a different agonist.
Therefore, on the basis of toll like receptors and dendritic
cells, we understand the role of the immune system in acute
as well as chronic inflammation as well as pathological
processes, new opportunities have arisen to develop
effective therapies for a wide range of disorders and
diseases.
3. Toll like receptors
Toll like receptors is first being identified and described in
the fruit fly Drosophila melanogaster and have proven to
be of great interest to immunologists interested in the
vaccine development. Toll like receptors belong to a class
of molecules known as pattern recognition receptors. The
receptors for the ligands belonged to the components of
pathogenic microbes and are often called pathogen-
associated molecular patterns. In human, at least 10 Toll
like receptors have been discovered in humans (TLR1-10)
[3, 4, 5]. With the exception of TLR2, toll like receptors
initiate signaling by homodimerization. TLR2 forms a
linkage between TLR1 or TLR6. The signaling pathways of
TLRs leading to production of proinflammatory cytokines
are extensively studied and largely defined. The main target
of toll like receptors is to induce Th1 and Th2 type of
cytokines, which is already validated and successfully being
targeted in the animal experiments and also represented
better set of targets than cytokines or other downstream
processes. Toll like receptors are specific for various
conserved pathogen associated molecular patterns: LPS by
TLR-4, flagellin by TLR-5, microbial DNA and RNA by
Sushama R Chaphalkar et al. / WJPBT, 2014, 1(1): 1114
World Journal of Pharmacy and Biotechnology 13
TLR 3, 7, and 8. The first identified TLRs as TLR4 ligand
LPS for example, is a constituent of cell membranes of
Gram-negative bacteria [6]. LPS interaction with TLR4
involves at least two other proteins. LPS (agonist of TLR4)
binds first to lipopolysaccharide binding protein in serum
[7] and is then transferred to CD14 [8]. The mechanism of
CD14 marker is to enhance the sensitivity of the TLR4
signaling complex and reduced the binding affinity for LPS
to picomolar concentrations [9]. Mice without CD14
marker are resistant to endotoxic shock [10].
T-helper cells and cytokines
T-helper cells are divided into a number of subsets
including Th1, Th2 and Th17 [11]. The main cytokine
involved in dendritic cell i.e. IL-12 which promotes IFN-
induction by T cells and natural killer cells and polarization
towards Th1 type of immune cells [12]. So, it is important
to develop or synthesize novel agonists to maintain the
lipophilic as well as hydrophilic balance to promote Th1
type of immune response for protection against intracellular
pathogens including Tuberculosis [13] and malaria [14]. On
the other hand, Toll-like receptor agonists particularly CpG
oligodeoxynucleotides, promote IL-12 secretion by
dendritic cells and is able to induce Th1 type of immune
responses [15].
Th2 cells mediate the activation and maintenance of the
humoral antibody titre against extracellular pathogens i.e.
parasites, allergens and bacteria. Th2 cells producing
various cytokines such as IL-4, IL-5, IL-6, IL-9, IL-13, and
IL-17E which is responsible for promoting antibody
production, activation of eosinophil (allergy conditions,
control the regulation of B cell class-switching to IgE) and
inhibition of several macrophage functions (interferon
gamma and tumor necrosis factor alpha), thus providing
phagocyte-independent protective responses. Functionally,
Th2 cytokines and its receptors have already expressed on
the body and various cell types. Th2 cells stimulate and
recruit specialized subsets of immune cells, i.e. eosinophils
and basophils to the site of infection due to allergens
leading to tissue eosinophilia and mast cell hyperplasia.
Additionally, Th2 cells are also known to be responsible for
the development of asthma and other allergic inflammatory
diseases.
Apart from this, Th17 cells also played an important role in
protective immunity against extracellular bacteria [16] and
these cells produce IL-17A, IL-17F, IL-21 and IL-22, and
these responses are promoted by the cytokines IL-6, IL-1
and IL-23 [17]. Using this knowledge, specific novel
agonists of toll like receptors can be developed against
vaccine antigen to promote the secretion of Th17-polarizing
cytokines by dendritic cells. Since Th17 cells are also play
an important role in autoimmune reactions, there are some
points regarding the potential danger of adjuvants to
promote Th17 cells. However, it is assumed that a number
of common infections and vaccines in widespread clinical
use can promote Th17 cells.
Figure 1: Dendritic cell, costimulatory molecules and Toll like receptor agonists
4. Conclusion
In summary distinct TLR agonists into subunit vaccine
doubled the magnitude of the T
H
1 response and enhanced
the protective efficacy. Until an effective vaccine against
any vaccine antigen is developed and tested clinically in
efficacy studies it will be impossible to validate correlates
of protection
Sushama R Chaphalkar et al. / WJPBT, 2014, 1(1): 1114
World Journal of Pharmacy and Biotechnology 14
5. References
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2. Otero M.J. Dendritic cells and their Toll-like
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A. Beutler, Jules A. Hoffmann, and Ralph M.
Steinman. Contributions to Science, 2012, 8(1):
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3. Schnare M., Rollinghoff M., Qureshi S. Toll-like
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4. Kumar H., Kawai T., Akira S. Toll-like receptors
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6. Medzhitov R., Preston-Hurlburt P., and Janeway
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Coussens N.P., Dockstader W., Ramaswamy S.,
and Weiss J.P. Isolation of an endotoxin-MD-2
complex that produces Toll-like receptor 4-
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deficient mice. Immunity, 1996, 4: 407-414.
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