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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 106, Num. s1, 2011, pp. 172-178
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Memórias do Instituto Oswaldo Cruz, Vol. 106, Special Issue, pp. 172-178
Original Article
Induction
and maintenance of protective CD8+ T cells against malaria liver
stages: implications for vaccine development
Sze-Wah Tse;
Andrea J Radtke; Fidel Zavala +
W Harry Feinstone
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg
School of Public Health, Johns Hopkins Malaria Research Institute, Johns Hopkins
University, Baltimore, Maryland, USA
+ Corresponding author:fzavala@jhsph.edu
Received 30 March
2011
Accepted 20 May 2011
Code Number: oc11155
Abstract
CD8+ T cells against malaria liver stages represent a major protective immune mechanism
against infection. Following induction in the peripheral lymph nodes by dendritic
cells (DCs), these CD8+ T cells migrate to the liver and eliminate
parasite infected hepatocytes. The processing and presentation of sporozoite
antigen requires TAP mediated transport of major histocompatibility complex
class I epitopes to the endoplasmic reticulum. Importantly, in DCs this process
is also dependent on endosome-mediated cross presentation while this mechanism
is not required for epitope presentation on hepatocytes. Protective CD8+ T cell responses are strongly dependent on the presence of CD4+ T
cells and the capacity of sporozoite antigen to persist for a prolonged period
of time. While human trials with subunit vaccines capable of inducing antibodies
and CD4+ T cell responses have yielded encouraging results, an effective
anti-malaria vaccine will likely require vaccine constructs designed to induce
protective CD8+ T cells against malaria liver stages.
Key words:
malaria - CD8+ T cell - vaccine - sporozoites
Given the enormous
disease burden of malaria, effective control strategies, such as the development
of a protective vaccine, are urgently needed. The liver stage of malaria is
an attractive vaccine target because a small number of parasites productively
invade the liver to establish infection in hepatocytes which express class I
major histocompatibility complex (MHC) and, therefore, are ideal targets of
protective immunity mediated by CD8+ T cells. This review highlights
recent studies conducted in our laboratory, and by colleagues in the field,
that have expanded our knowledge of protective CD8+ T cell responses
against liver stages. In addition, we will discuss the implications of these
studies on the development of an effective malaria vaccine and will critically
examine the advantages and disadvantages of existing vaccine strategies.
Priming of CD8+
T cells - Protective immunity to rodent malaria parasites was first achieved
in mice by immunization with radiation attenuated sporozoites (Nussenzweig et
al. 1967). These studies were later extended to humans using irradiated mosquitoes
infected with Plasmodium falciparum sporozoites and have provided the
rationale for the development of an irradiated sporozoite vaccine (Clyde et
al. 1973). In experimental models, protection against live sporozoite challenge
was shown to require antigen-specific CD8+ T cells as in vivo depletion
of CD8+ T cells completely abrogated sterile immunity in mice infected
with rodent malaria parasites (Schofield et al. 1987, Weiss et al. 1988). Most
importantly, we have shown that CD8+ cells against defined epitopes
of Plasmodium berghei and Plasmodium yoelii circumsporozoite (CS)
protein strongly inhibited the development of liver stage parasites (Romero
et al. 1989, Rodrigues et al. 1991). Subsequently, transgenic mice expressing
a T-cell receptor (TCR) specific for the MHC l restricted epitope of the CS
of P. yoelii have been developed and used to characterize the
induction of effector CD8+ T cells (Sano et al. 2001, Carvalho et
al. 2002). Using this system, we demonstrated that malaria-specific CD8+
T cells are primed in the skin-draining lymph nodes of mice (Chakravarty et
al. 2007). Following immunization by irradiated P. yoelii infected mosquitoes,
interferon gamma (IFN-γ)
producing CD8+ T cells were detected in the ear-draining lymph nodes
as early as 48 h after immunization; however, significant responses in the spleen,
liver and liver-draining lymph nodes were not observed until 72 h post-immunization.
A significant reduction in the anti-sporozoite CD8+ T cell response
was observed in animals that had their draining lymph nodes removed prior to
sporozoite immunization. Together, these results demonstrate a critical role
for the skin-draining lymph nodes in the priming of CD8+ T cells
protective against pre-erythrocytic stage parasites, but do not exclude a possible
contribution of liver associated antigen presenting cells in the presentation
of parasite antigens. A subset of liver resident dendritic cells (DCs), CD8α+CD11c+,
was shown to activate CD8+ T cells, as determined by the acquisition
of the CD44hiCD45RBlo phenotype and IFN-γ
production in vitro, following prime-boost intravenous immunizations with irradiated
P. berghei sporozoites (Jobe et al. 2009).
It is well established
that DCs play a critical role in the priming of Plasmodium specific CD8+
T cells (Jung et al. 2002, Plebanski et al. 2005, Chakravarty et al. 2007, Jobe
et al. 2009). Furthermore, several lines of evidence suggest a vital role for
cross presentation in the priming of CD8+ T cells by DCs. Pre-treatment
with Toll-like receptor (TLR) ligands can cause pre-maturation of DCs and subsequently
inhibit cross presentation to CD8+ T cells (Radhakrishnan et al.
2005, Wilson et al. 2006). Accordingly, activation of CD8+ T cells
was significantly reduced in animals that had been treated with CpG (a TLR-9
ligand) prior to immunization with irradiated P. yoelii sporozoites.
In a recent study, we expanded on the requirement for cross presentation using
two different in vivo methodologies and a mutant transgenic parasite. To study
the in vivo processing requirements of CS by DCs and hepatocytes, our laboratory
generated P. berghei parasites expressing a mutant CS protein with the
H-2Kb SIINFEKL epitope (P. berghei CS5M). Studies
with this parasite and TCR transgenic CD8+ T cell specific for this
H-2Kb epitope (Hogquist et al. 1994) revealed a requirement for the
TAP transporter and the endosome-to-cytosol pathway in antigen presentation
by DCs. In this study, the induction phase of CD8+ T cells was
evaluated in mice defective in endosomal function and cross-presentation (3d)
(Tabeta et al. 2006) and also in mice depleted of cross-presenting DCs following
in vivo cytochrome c (cyt c) treatment (Lin et al. 2008, Farrand
et al. 2009, Qiu et al. 2009). Significant reductions in CD8+ T cell
priming were observed in both 3d mice and cyt c treated mice (Cockburn
et al. 2011).
Cross presentation
is greatly enhanced by microbial molecular patterns, especially TLR ligands
(Beutler et al. 2003, Kopp & Medzhitov 2003, Hemmi & Akira 2005, Burgdorf
et al. 2008). Following receptor recognition of microbial moieties, DCs undergo
maturation and migrate to the secondary lymphoid organs where they present antigen
to T cells. DC maturation, characterized by high levels of MHC and T cell costimulatory
molecules, is critical for the optimal priming of naÏve T cells to pathogen-derived
antigen (Janeway & Medzhitov 2002, Wilson & Villadangos 2005, Steinman
& Hemmi 2006, López-Bravo & Ardavín 2008). To date, a
sporozoite-derived TLR ligand has not been identified, although TLRs have been
shown to recognize different components of malaria blood stages of P. falciparum
and P. berghei (Pichyangkul et al. 2004, Coban et al. 2005, Krishnegowda
et al. 2005, Parroche et al. 2007, Couper et al. 2010, Wu et al. 2010). In addition
to TLRs, intracellular pathogens and "danger signals" are sensed by cytosolic
Nod-like receptors and result in the formation of the inflammasome, a multi-protein
complex responsible for the processing of the pro-inflammatory cytokines interleukin
(IL)-1β
and IL-18 (Fritz et al. 2006, Martinon et al. 2007, Lamkanfi & Dixit 2009,
Schroder & Tschopp 2010). Prior to establishing infection in the liver,
sporozoites must traverse several cells and thus may conceivably trigger an
innate immune response via these intracellular receptors. An understanding of
the innate immune signaling pathways activated against sporozoite antigens will
provide critical insights into the induction of protective CD8+ T
cell responses and may influence the selection of an effective vaccine adjuvant.
Another major question
in the priming of anti-sporozoite CD8+ T cell responses is the precise
site of antigen capture by DCs and its delivery to the skin-draining lymph nodes.
In 2006, Amino et al. (2006) performed a quantitative analysis of sporozoite
movement in the skin using green fluorescent protein-tagged sporozoites. Intriguingly,
25% of inoculated sporozoites were found to associate with DCs in the lymph
nodes. The majority of intradermally inoculated sporozoites resides in the skin
for over 1 h and exit the skin at a slow trickle (Sinnis & Coppi 2007, Yamauchi
et al. 2007). These studies indicate that sporozoite migration to the draining
lymph nodes, in addition to parasites deposited in the skin, can provide antigens
to the lymph nodes draining the site of inoculation. This finding raises
the following questions: how and where do DCs acquire sporozoite antigen? One
possibility is that sporozoite antigen is acquired in the dermis by skin-resident
DCs that then migrate to the lymph nodes and present antigen directly to naive
CD8+ T cells. At least three distinct subsets of skin-resident migratory
DCs have been characterized: Langerhans cells, dermal DCs, and langerin+CD103+
dermal DCs (Heath & Carbone 2009). The recent identification of langerin+CD103+
dermal DCs, a subset of migratory DCs that plays a key role in cross-presenting
viral and self antigens (Bursch et al. 2007, Ginhoux et al. 2007, Poulin et
al. 2007, Bedoui et al. 2009), is especially intriguing given the requirement
for cross-presentation in the priming of anti-sporozoite CD8+ T cells.
Alternatively, dermal DCs could transfer skin-derived antigen to lymph node
resident DCs for CD8+ T cell priming as shown in studies using skin
infection with herpes simplex virus (Allan et al. 2006). Finally, it is also
possible that CD8+ T cell priming does not require skin-derived DCs,
but instead, requires direct processing and presentation of sporozoite antigen
by lymph-node resident DCs. Determination of the site of antigen capture and
the identification of the DC subset(s) responsible for inducing protective CD8+
T cell responses are important questions for malaria research.
Antigen recognition
by CD8+ T cells in the liver and effector mechanisms - Following
priming in the skin-draining lymph nodes, activated CD8+ T cells
migrate to the liver where they recognize antigen presented by hepatocytes and
eliminate the infected cell (Chakravarty et al. 2007). A proteasome-dependent
pathway was shown to be required for the in vitro processing of P. berghei
CS by infected and traversed mouse hepatocytes (Bongfen et al. 2007, 2008).
Our studies using bone marrow chimeras revealed a requirement for direct peptide
recognition between effector CD8+ T cells and host parenchymal liver
cells as memory CD8+ T cells were unable to eliminate infected hepatocytes
bearing a non-cognate MHC. Importantly, antigen presentation by cells of the
hematopoietic lineage was not required for the effector function of CD8+
T cells (Chakravarty et al. 2007). Using the transgenic P. berghei parasite
expressing SIINFEKL, the H-2Kb restricted epitope (P. berghei
CS5M) mentioned above (Cockburn et al. 2011) and genetically
deficient mice of the C57Bl/6 background we were able to gain further insight
into the antigen presentation pathway in hepatocytes. We evaluated the requirement
for the TAP dependent pathway for antigen presentation in hepatocytes by transferring
activated SIINFEKL specific CD8+ T cells to TAP-1 deficient animals.
Effector CD8+ T cells were unable to inhibit parasite development
in the livers of TAP-1 deficient animals. In contrast, effector cells efficiently
eliminated liver stages in mice deficient in endosome function and cross-presentation
(3d and cyt c treated mice). Therefore, endosomes are not required for
the presentation of sporozoite antigen in infected hepatocytes. Additional studies
also indicated that the conserved Plasmodium export element and vacuolar
translocation signal, which have been shown to be required for the export of
Plasmodium proteins into the erythrocyte cytosol (Hiller et al. 2004,
Marti et al. 2004), may not be required for CS antigen presentation to CD8+
T cells (Cockburn et al. 2011). Further investigation of the mechanism by which
CS enters the cytosol of infected hepatocytes is critical for a fundamental
understanding of the antigen presentation requirements for CD8+ T
cell mediated elimination of liver stages.
To date, the effector
mechanisms used by CD8+ T cells to eliminate liver stage parasites
are not clearly defined and are likely to be redundant. The two main cytotoxic
mechanisms of CD8+ T cells, release of perforin/granzyme and Fas/FasL
interactions, are dispensable for parasite elimination. Mice deficient in these
two mechanisms (Renggli et al. 1997) as well as CD8+ T cells lacking
one or both mechanisms (Morrot & Zavala 2004) were still able to eliminate
Plasmodium liver stages. In addition, a recent study indicates a Plasmodium-species
specific difference in the effector mechanisms used by memory CD8+
T cells to eliminate liver stage parasites. In particular, protection against
P. berghei and P. yoelii liver stage parasites was dependent on
IFN-γ
and tumor necrosis factor alpha (TNF-α);
however, perforin was also required to confer protection against P. yoelii
(Butler et al. 2010). Other studies using genetically attenuated P. yoelii
parasites revealed a partial requirement for perforin as well as IFN-γ
for protective immunity (Trimnell et al. 2009). These studies, along with several
others (Weiss et al. 1992, Seguin et al. 1994, Doolan & Hoffman 2000, Mueller
et al. 2007), demonstrate a critical role for IFN-γ
in CD8+ T cell mediated protection. However, the authors base their
conclusions on the global ablation of IFN-γ
using neutralizing antibodies or genetic knockouts that are severely affected
in other aspects of the immune response downstream of IFN-γ
deficiency. Our studies determined that despite systemic inhibition of IFN-γ
and TNF-α,
mice were still protected against live P. yoelii sporozoites (Rodrigues
et al. 1991). Similar results were obtained using adoptive transfer of IFN-γ
deficient CS-specific CD8+ T cells (Chakravarty et al. 2008).In summary,
the protective mechanisms of CD8+ T cell mediated immunity have yet
to be precisely defined and may differ between model systems and the genetic
background of the host.
Generation of
CD8+ T cell memory population: role of CD4+ T cells and
persisting antigen - Sporozoite development in the liver is brief, lasting
48 h in rodent malaria infections, and precedes the time required for the infiltration
of memory CD8+ T cells. It seems clear that memory T cell populations
residing in the liver of the immunized host provide the first line of defence
against subsequent infection and are therefore the key players of the recall
response. Over the past few years, our laboratory has determined critical factors
in the generation of a robust, stable memory population. In particular, CD4+
T cell help was shown to be required for CD8+ T cell memory responses
against malaria (Carvalho et al. 2002, Overstreet et al. 2011). CD4+
T cell depletion or treatment with IL-4 neutralizing antibodies prior to irradiated
sporozoite immunization did not impair CD8+ T cell expansion, but
resulted in premature contraction of the effector pool (Carvalho et al. 2002,
Morrot et al. 2005). Therefore, CD4+ T cell help appears to be important
for maximal clonal expansion of CD8+ T cells. Previous reports in
other systems (Janssen et al. 2003, Shedlock & Shen 2003, Sun & Bevan
2003) suggest that an absence of CD4+ T cell help contributes to
defective cytokine production, killing and re-expansion of memory CD8+
T cells. We tested whether the "helpless" CD8+ T cells generated
by irradiated sporozoite immunization also have defective functional properties.
Surprisingly, although the memory size of the "helpless" CD8+ T cells
was much smaller, the functionality of "helpless" CD8+ T cells was
not impaired, as the production of IFN-γ,
TNF-α
and IL-2, as well as cytotoxic degranulation, were similar between "helped"
and "helpless" CD8+ T cells (Overstreet et al. 2011). This implied
that CD4+ T cells, while being critical to achieve a large CD8+
T cell response, play a minor role, if any, in the development of the functional
properties of these cells. Although these "helpless" CD8+ T cells
were functional, they failed to protect the host from live parasite challenge
because of their low numbers. This finding is consistent with recent reports
indicating that a large number of circulating anti-malaria T cells is necessary
for sterile immunity (Schmidt et al. 2008).
In addition to
CD4+ T cell help, prolonged antigen presentation is also crucial
for maximal expansion of effector T cells. We demonstrated that continuous antigen
presentation occurs, up to two months after immunization with irradiated sporozoites
(Cockburn et al. 2010). This observation is quite striking considering that
irradiated sporozoites are not able to undergo proliferation, and they are not
known to differentiate beyond early liver stages (Silvie et al. 2002). Apparently,
the parasite antigen does not persist as other forms of parasite or exo-erythrocytic
remnants because treatment with primaquine to eliminate early liver stage parasites
has no effect on continuous antigen presentation. We also determined that professional
antigen presenting cells are responsible for trapping antigens, although the
identity of the cell types involved in presenting persisting antigens is unclear
and remains an area of further investigation. Persisting antigen may be required
for renewing and maintaining the memory CD8+ T cell population as
naÏve cells, such as recent thymic emigrants, can be primed by persisting
antigens. It is important to highlight that this prolonged antigen presentation
does not induce CD8+ T cell exhaustion as described in some chronic
viral infection models (Klenerman & Hill 2005, Shin & Wherry 2007).
On the contrary, prolonged antigen presentation is fully capable of inducing
effector T cell differentiation. Given that optimal development of protective
immunity appears to require prolonged antigen persistence, this result has direct
implications for immune responses in endemic areas where people are exposed
to sporozoite antigen on a regular basis.
Implications
for the development of pre-erythrocytic vaccines - It is well established
that immunization with irradiated sporozoites, in both rodent models and limited
human studies, remains the most effective malaria vaccine. However, preparing
sporozoites for immunization is a difficult task and a very labor-intensive
process. More importantly, all procedures leading to sporozoite purification
must ensure the full viability of the sporozoite preparation as dead parasites
do not induce effector CD8+ T cell responses (Hafalla et al. 2006).
These technical limitations have favoured the development of subunit vaccines
composed of protective malaria antigens such as CS. CS-based subunit vaccines
can be formulated as the following: synthetic peptides coupled to carrier proteins,
synthetic peptide polymers containing the B and/or T cell epitope of CS, DNA
constructs and recombinant proteins.
One of the simplest
subunit vaccine concepts is peptide-based vaccines. When mice were immunized
with the SYVPSAEQI peptide (the CD8+ T cell epitope in CS of P.
yoelii) alone, the CD8+ T cells strongly proliferated, indicating
that the peptide itself is strongly immunogenic. However, the expanded CD8+
T cells did not survive (Overstreet et al. 2010). In all likelihood, certain
innate signals required for the induction and development of effector CD8+
T cells are likely absent in peptide-based vaccines. In recent studies we evaluated
whether the administration of TLR agonists can rescue the widespread cell death
observed after initial priming. Interestingly, CpG is capable of enhancing the
magnitude of CD8+ T cell priming, yet CpG treatment did not enhance
the survival of CD8+ T cells. In addition, we saw a greater effector
population 10 days after peptide with CpG immunization in B cell deficient mice,
which suggests that B cells have an inhibitory role in peptide immunization
(Overstreet et al. 2010). Indeed, the suppressive role of B cells, through the
up-regulation of IL-10 and TGF-β,
has been suggested in other systems (Parekh et al. 2003, Lenert et al. 2005).
The exact mechanisms by which B cells regulate CD8+ T cell priming
and survival after peptide immunization remain to be elucidated.
Another example
of a CS-based subunit vaccine is the RTS,S vaccine: a subunit vaccine composed
of the repeat domain and C-terminal flanking regions (amino acids 207-395) of
the P. falciparum CS expressed in the hepatitis B virus-like particle
(VLP) (Cohen et al. 2010). When administered with adjuvant, the protection provided
by the RTS,S vaccine only achieved about 30-50% efficacy at best. The protective
mechanisms mediated by RTS,S appear to be antibody-dependent; however, IFN-γ
secreting CD4+ T cells may also contribute to protection (reviewed
in Good & Doolan 2010). Moreover, the RTS,S vaccine fails to induce significant
CD8+ T cell responses (Kester et al. 2009), possibly due to the fact
that VLPs are known to be poor primers of CD8+ T cells.
It has been suggested
that protection depends on the size of the memory CD8+ T cell pool
(Schmidt et al. 2008). Expansion of existing memory populations may therefore
enhance the protective immunity conferred by CD8+ T cells. Though
subunit vaccines have achieved modest success, they remain a valid vaccine option
if their effectiveness can be enhanced. In fact, we have demonstrated that CD8+
T cell mediated protection against sporozoite challenge could be achieved with
recombinant viral vectors using heterologous prime-boost regimens (Li et al.
1993). Antigen persistence may enhance the efficacy of subunit vaccines. This
is an interesting area of future research and it would be necessary to determine
how long antigen is presented after immunization with current subunit vaccine
formulations. In summary, the partial protection provided by subunit vaccines
suggests that improved adjuvant formulations, vaccine constructs and heterologous
prime-boost regimens are required to enhance the immunogenicity of CS-based
vaccine approaches.
In addition to
the continued development and optimization of subunit vaccines, there has been
a renewed interest in whole parasite vaccines. Although these vaccines are difficult
to manufacture, they may allow the generation of a broad, protective immune
response against multiple parasite antigens at once, rather than the few targeted
in subunit vaccines. The development of an irradiated P. falciparium
vaccine, based on cryopreserved sporozoites extracted from salivary glands of
infected mosquitoes, has been proposed (Luke & Hoffman 2003) and is currently
being considered. However, poor immunogenicity due to poor survival of parasites
after freezing may present a major hurdle for the implementation of this type
of vaccine.
Recent knowledge
in Plasmodium genome sequences and advancement in transfection technologies
have led to the development of genetically attenuated sporozoites (GAS), which
are theoretically similar to the radiation attenuated sporozoite approach. In
fact these mutant parasites are capable of inducing long-lasting immunity in
mice (Mueller et al. 2005, Tarun et al. 2007). When targeted appropriately,
some mutant parasites are able to develop into large schizonts before undergoing
growth arrest in the liver. These parasites may allow more liver stage antigens
to be presented to the immune system and perhaps induce a more polyclonal immune
response than irradiated sporozoites (Vaughan et al. 2010). However, evidence
indicates that incomplete attenuation of certain strains of GAS represents a
serious problem to this approach (Mueller et al. 2005, van Dijk et al. 2005).
In addition, as is the case for the preparation of a radiation attenuated vaccine,
large-scale manufacturing, extraction of parasites from infected mosquitoes,
cryopreservation and delivery of the vaccine are major technical challenges
for the production of whole parasite vaccines.
Since Plasmodium
parasites have several life stages, antigen selection will be crucial for the
development of an effective vaccine. Ideal protective antigens should be those
that are recognized by CD8+ T cells during priming in the lymph nodes
and on infected hepatocytes. Thus, the distinct requirements for antigen presentation
in DCs and hepatocytes have important implications for vaccine research. Specifically,
DCs are capable of acquiring antigens by phagocytosis and can therefore induce
CD8+ T cell responses to secreted as well as non-secreted antigens.
In contrast, hepatocytes can only present antigens in the cytosol of infected
or traversed cells. Therefore, optimal targets of protective immunity should
include pre-erythrocytic antigens that are both processed by DCs and presented
by infected hepatocytes to effector cells, the latter being the most critical
requirement for parasite elimination. It is generally accepted that there are
other protective antigens in addition to CS. In fact, mice tolerized to CS still
develop protective immunity after immunization with irradiated sporozoites (Kumar
et al. 2006). Moreover, immune responses to a wide range of parasite antigens
were observed in human volunteers immunized with irradiated sporozoites (Doolan
et al. 2003). There is a consensus that an efficient malaria vaccine should
target blood stages and sexual stages in addition to pre-erythrocytic stages
of the parasite. The advancement in transcriptional profiling of all Plasmodium
stages may help to identify novel antigens that can be incorporated into the
development of multi-stage vaccines against human malaria infection.
Acknowledgements
To Bloomberg Family
Foundation, for the support, and to Omotooke Arojo, for her critical review
of the manuscript.
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