Low CD4+ T cell responses to the C-terminal region of the malaria merozoite surface protein-1 may be attributed to processing within distinct MHC class II pathways

Quin, Stuart; Cross, Caroline; Berg, Matthias; Lindo, Vivian; Stockinger, Brigitta; Langhorne, Jean

doi:10.1002/1521-4141(200101)31:1<72::aid-immu72>3.3.co;2-q

Cited by 12 publications

(30 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The conformational epitopes created by the correct folding of the MSP1 19 fragment are essential for the induction of functionally relevant inhibitory antibodies [59], yet these epitopes are poorly immunogenic [33], most likely because disulfide bond rich moieties inhibit the protease activity essential for antigen processing [39]. The cellular response to MSP1 19 seems to improve when a denatured recombinant protein is used as immunogen [35]. Several approaches have been used to enhance the immunogenicity of the MSP1 19 fragment that include the conjugation of exogenous T cell epitopes to a MSP1 19 fusion protein [60], the fusion of MSP1 19 to novel protein adjuvants [61], the genetic linkage to hepatitis B virus surface protein [62, 63] or the genetic linkage to promiscuous T cell epitopes [40, 42, 64].…”

Section: Discussionmentioning

confidence: 99%

“…T cell reactivity to MSP1, elicited by natural exposure to malaria parasites, is directed toward epitopes located in the amino terminal portion of the protein [33–35]. The compact tertiary structure of the MSP1 19, which is maintained by several disulfide bridges [22, 36, 37], restricts antigen processing and impairs T cell responses to this fragment [38].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic linkage of autologous T cell epitopes in a chimeric recombinant construct improves anti-parasite and anti-disease protective effect of a malaria vaccine candidate

Singh

Cabrera-Mora

Jiang

et al. 2010

Vaccine

View full text Add to dashboard Cite

We have reported the design of polyvalent synthetic and recombinant chimeras that include promiscuous T cell epitopes as a viable delivery system for pre-erythrocytic subunit malaria vaccines. To further assess the ability of several Plasmodium T cell epitopes to enhance vaccine potency, we designed a synthetic gene encoding four P. yoelii merozoite surface protein 1 (PyMSP1) CD4 + promiscuous T cell epitopes fused in tandem to the homologous carboxyl terminal PyMSP1 19 fragment. This Recombinant Modular Chimera (PyRMC-MSP1 19 ) was tested for immunogenicity and protective efficacy in comparative experiments with a recombinant protein expressing only the PyMSP1 19 fragment. Both proteins induced comparable antibody responses. However PyRMC-MSP1 19 elicited higher anti-parasite antibody titers and more robust protection against both hyperparasitemia and malarial anemia. Most importantly, passive transfer of anti-PyRMC-MSP1 19 , but not anti-PyMSP1 19 antibodies protected against heterologous challenge. These studies show that protective efficacy can be significantly improved by inclusion of an array of autologous promiscuous T cell epitopes in vaccine constructs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic linkage of autologous T cell epitopes in a chimeric recombinant construct improves anti-parasite and anti-disease protective effect of a malaria vaccine candidate

Singh

Cabrera-Mora

Jiang

et al. 2010

Vaccine

View full text Add to dashboard Cite

show abstract

“…Few studies have determined the pathways used for presentation of multiple epitopes from candidate vaccine antigens 42,43 . We have previously shown that CD4 T‐cell epitopes from other bacterial proteins include representatives of both the classical and recycling pathways, depending on the structural context of the particular epitope 22–24 .…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of major histocompatibility complex class II‐restricted processing and presentation of the V antigen of Yersinia pestis

Shim¹,

Musson²,

Harper³

et al. 2006

Immunology

View full text Add to dashboard Cite

We mapped mouse CD4 T-cell epitopes located in three structurally distinct regions of the V antigen of Yersinia pestis. T-cell hybridomas specific for epitopes from each region were generated to study the mechanisms of processing and presentation of V antigen by bone-marrow-derived macrophages. All three epitopes required uptake and/or processing from V antigen as well as presentation to T cells by newly synthesized major histocompatibility complex (MHC) class II molecules over a time period of 3-4 hr. Sensitivity to inhibitors showed a dependence on low pH and cysteine, serine and metalloproteinase, but not aspartic proteinase, activity. The data indicate that immunodominant epitopes from all three structural regions of V antigen were presented preferentially by the classical MHC class II-restricted presentation pathway. The requirement for processing by the co-ordinated activity of several enzyme families is consistent with the buried location of the epitopes in each region of V antigen. Understanding the structure-function relationship of multiple immunodominant epitopes of candidate subunit vaccines is necessary to inform choice of adjuvants for vaccine delivery. In the case of V antigen, adjuvants designed to target it to lysosomes are likely to induce optimal responses to multiple protective T-cell epitopes.

show abstract

“…DCs incubated with Plasmodium ‐infected RBCs or DCs taken from infected mice can present parasite peptides to CD4 T cells (33, 46, 51). Our studies (54) with bone marrow‐derived DCs and those of Ludendyk et al .…”

Section: The Effect Of Dc–parasite Interaction On the T‐cell Responsementioning

confidence: 99%

“…Both peptides required processing of MSP1 to be presented. However, a response by the T‐cell hybridoma recognizing the peptide in the 19‐kDa fragment was only detectable after 7 h of incubation of the DCs with either the protein or infected erythrocytes, compared to the response of the hybridoma recognizing the peptide in the less complex soluble fragment, which occurred within 2 h. Further analysis showed that processing of the 19‐kDa fragment to produce the peptide required the de novo synthesis of MHC class II, whereas the peptide in the soluble fragment was processed in the recycling pathway (46). Reduction of the disulfide bonds within the 19‐kDa fragment decreased the time required for presentation () and rendered the protein also susceptible to processing in this recycling pathway (46).…”

Section: Plasmodium Antigens and Processingmentioning

confidence: 99%

Dendritic cells, pro‐inflammatory responses, and antigen presentation in a rodent malaria infection

Langhorne¹,

Albano²,

Hensmann³

et al. 2004

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

An infection of mice with Plasmodium chabaudi is characterized by a rapid and marked inflammatory response with a rapid but regulated production of interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). Recent studies have shown that dendritic cells (DCs) are activated in vivo in the spleen, are able to process and present malaria antigens during infection, and may provide a source of cytokines that contribute to polarization of the CD4 T-cell response. P. chabaudi-infected erythrocytes are phagocytosed by DCs, and peptides of malaria proteins are presented on major histocompatibility complex (MHC) class II. The complex disulfide-bonded structure of some malaria proteins can impede their processing in DCs, which may affect the magnitude of the CD4 T-cell response and influence T-helper 1 (Th1) or Th2 polarization. DCs exhibit a wide range of responses to parasite-infected erythrocytes depending on their source, their maturational state, and the Plasmodium species or strain. P. chabaudi-infected erythrocytes stimulate an increase in the expression of costimulatory molecules and MHC class II on mouse bone marrow-derived DCs, and they are able to induce the production of pro-inflammatory cytokines such as IL-12, TNF-alpha, and IL-6, thus enhancing the Th1 response of naïve T cells. IFN-gamma and TNF-alpha play a role in both protective immunity and the pathology of the infection, and the inflammatory disease may be regulated by IL-10 and transforming growth factor-beta. It will therefore be important to elucidate the host and parasite molecules that are involved in activation or suppression of the DCs and to understand the interplay between these opposing forces on the host response in vivo during a malaria infection.

show abstract

Low CD4+ T cell responses to the C-terminal region of the malaria merozoite surface protein-1 may be attributed to processing within distinct MHC class II pathways

Cited by 12 publications

References 0 publications

Genetic linkage of autologous T cell epitopes in a chimeric recombinant construct improves anti-parasite and anti-disease protective effect of a malaria vaccine candidate

Genetic linkage of autologous T cell epitopes in a chimeric recombinant construct improves anti-parasite and anti-disease protective effect of a malaria vaccine candidate

Mechanisms of major histocompatibility complex class II‐restricted processing and presentation of the V antigen of Yersinia pestis

Dendritic cells, pro‐inflammatory responses, and antigen presentation in a rodent malaria infection

Contact Info

Product

Resources

About