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Peptide Dose and/or Structure in Vaccines as a Determinant of T Cell Responses.

Leggatt GR - Vaccines (Basel) (2014)

Bottom Line: While T cells recognise the complex of peptide and major histocompatibility complex (MHC) at the cell surface, changes in the dose and/or structure of the peptide component can have profound effects on T cell activation and function.Altering the structure of the peptide ligand can also influence the selection and function of peptide-specific T cell clones.In this review, we will explore the evidence that the choice of peptide dose or the structure of the peptide are critical parameters in an effective vaccine designed to activate T cells.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane QLD 4102, Australia. g.leggatt@uq.edu.au.

ABSTRACT
While T cells recognise the complex of peptide and major histocompatibility complex (MHC) at the cell surface, changes in the dose and/or structure of the peptide component can have profound effects on T cell activation and function. In addition, the repertoire of T cells capable of responding to any given peptide is variable, but broader than a single clone. Consequently, peptide parameters that affect the interaction between T cells and peptide/MHC have been shown to select particular T cell clones for expansion and this impacts on clearance of disease. T cells with high functional avidity are selected on low doses of peptide, while low avidity T cells are favoured in high peptide concentrations. Altering the structure of the peptide ligand can also influence the selection and function of peptide-specific T cell clones. In this review, we will explore the evidence that the choice of peptide dose or the structure of the peptide are critical parameters in an effective vaccine designed to activate T cells.

No MeSH data available.


Summary of the effects of variant, low and high dose peptide on effector T cell responses.
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vaccines-02-00537-f001: Summary of the effects of variant, low and high dose peptide on effector T cell responses.

Mentions: Many of the traditional vaccines against infectious disease have involved the use of attenuated live or killed organisms with excellent results such as the elimination of smallpox [1,2]. The use of whole organisms allows for the display of multiple antigenic determinants with a subset of these antigens often dominating the immune response. Given the efficacy of these established vaccines, it appears that nature provides these selected epitopes in the context of the whole organism at the appropriate dose and timing to allow efficient T and B cell priming. In particular, many of these vaccines rely on the development of neutralising antibody which may have flexible requirements for epitope dose in vivo above some minimum threshold [3]. In contrast, infectious agents for which no vaccine currently exists, such as HIV, are likely to have a greater dependence on T cell mediated clearance [4,5]. The activation of naive T cells in lymphoid organs is most efficiently achieved by dendritic cells (DCs). The engagement of pathogen recognition receptors (such as Toll-like receptors or TLRs) on the surface of tissue resident DCs leads to their maturation and migration to lymphoid organs. Here, the matured DCs present MHC/peptide complexes along with co-stimulatory ligands and cytokines to activate naive T cells and enable their conversion into effector or memory T cells. An efficient and appropriate conversion of naive T cells into effector/memory T cells is at the heart of current vaccine development. An early study showed that ovalbumin peptide delivered intravenously was able to tolerise peptide-specific CD4 T cells while the same peptide administered in complete Freund’s adjuvant via a subcutaneous site generated peptide-specific memory T cells [6]. This highlights the importance of peptide context in vaccine design and many vaccine studies are now focused on combining peptide with appropriate co-stimulatory molecules and a pro-inflammatory cytokine environment through the use of different adjuvants, delivery vectors and immunisation routes [7,8,9,10,11]. It is unlikely that any one combination of these variables will lead to a “universal” vaccine platform given the diversity of infection pathways utilized by pathogens. Aside from important co-stimulatory/cytokine considerations in vaccine development, there is also a central role for peptide in dictating the TCR signaling which leads to T cell proliferation and effector function. Several of the infectious diseases that require vaccine targeting are chronic infections that induce high or chronic loads of antigen. Under these circumstances, T cells can become anergised, exhausted or die of apoptosis [12,13,14]. Early in vitro experiments measuring the T cell response (likely CD4 T cells) to antigen have shown that too much antigen results in inhibition of the T cell proliferative response [15]. A similar high dose inhibition has also been documented for CD8 T cells [16]. So, while the effector function, measured as cytotoxicity or cytokine release, does not generally diminish with increasing peptide concentration, the ability of the T cell clone to divide and expand can be compromised. If mirrored in vivo, this is likely to affect the available T cell repertoire and subsequent pathogen clearance. Changing the peptide structure, as occurs in the natural viral variants arising during influenza infection, will also alter the responding repertoire of T cells either to allow immune escape or to establish a cross-reactive immune response [17]. This review will focus on studies which have examined the effects of peptide dose and/or structure on the repertoire of responding T cells and the outcomes for protection against disease (summarized in Figure 1).


Peptide Dose and/or Structure in Vaccines as a Determinant of T Cell Responses.

Leggatt GR - Vaccines (Basel) (2014)

Summary of the effects of variant, low and high dose peptide on effector T cell responses.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494221&req=5

vaccines-02-00537-f001: Summary of the effects of variant, low and high dose peptide on effector T cell responses.
Mentions: Many of the traditional vaccines against infectious disease have involved the use of attenuated live or killed organisms with excellent results such as the elimination of smallpox [1,2]. The use of whole organisms allows for the display of multiple antigenic determinants with a subset of these antigens often dominating the immune response. Given the efficacy of these established vaccines, it appears that nature provides these selected epitopes in the context of the whole organism at the appropriate dose and timing to allow efficient T and B cell priming. In particular, many of these vaccines rely on the development of neutralising antibody which may have flexible requirements for epitope dose in vivo above some minimum threshold [3]. In contrast, infectious agents for which no vaccine currently exists, such as HIV, are likely to have a greater dependence on T cell mediated clearance [4,5]. The activation of naive T cells in lymphoid organs is most efficiently achieved by dendritic cells (DCs). The engagement of pathogen recognition receptors (such as Toll-like receptors or TLRs) on the surface of tissue resident DCs leads to their maturation and migration to lymphoid organs. Here, the matured DCs present MHC/peptide complexes along with co-stimulatory ligands and cytokines to activate naive T cells and enable their conversion into effector or memory T cells. An efficient and appropriate conversion of naive T cells into effector/memory T cells is at the heart of current vaccine development. An early study showed that ovalbumin peptide delivered intravenously was able to tolerise peptide-specific CD4 T cells while the same peptide administered in complete Freund’s adjuvant via a subcutaneous site generated peptide-specific memory T cells [6]. This highlights the importance of peptide context in vaccine design and many vaccine studies are now focused on combining peptide with appropriate co-stimulatory molecules and a pro-inflammatory cytokine environment through the use of different adjuvants, delivery vectors and immunisation routes [7,8,9,10,11]. It is unlikely that any one combination of these variables will lead to a “universal” vaccine platform given the diversity of infection pathways utilized by pathogens. Aside from important co-stimulatory/cytokine considerations in vaccine development, there is also a central role for peptide in dictating the TCR signaling which leads to T cell proliferation and effector function. Several of the infectious diseases that require vaccine targeting are chronic infections that induce high or chronic loads of antigen. Under these circumstances, T cells can become anergised, exhausted or die of apoptosis [12,13,14]. Early in vitro experiments measuring the T cell response (likely CD4 T cells) to antigen have shown that too much antigen results in inhibition of the T cell proliferative response [15]. A similar high dose inhibition has also been documented for CD8 T cells [16]. So, while the effector function, measured as cytotoxicity or cytokine release, does not generally diminish with increasing peptide concentration, the ability of the T cell clone to divide and expand can be compromised. If mirrored in vivo, this is likely to affect the available T cell repertoire and subsequent pathogen clearance. Changing the peptide structure, as occurs in the natural viral variants arising during influenza infection, will also alter the responding repertoire of T cells either to allow immune escape or to establish a cross-reactive immune response [17]. This review will focus on studies which have examined the effects of peptide dose and/or structure on the repertoire of responding T cells and the outcomes for protection against disease (summarized in Figure 1).

Bottom Line: While T cells recognise the complex of peptide and major histocompatibility complex (MHC) at the cell surface, changes in the dose and/or structure of the peptide component can have profound effects on T cell activation and function.Altering the structure of the peptide ligand can also influence the selection and function of peptide-specific T cell clones.In this review, we will explore the evidence that the choice of peptide dose or the structure of the peptide are critical parameters in an effective vaccine designed to activate T cells.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane QLD 4102, Australia. g.leggatt@uq.edu.au.

ABSTRACT
While T cells recognise the complex of peptide and major histocompatibility complex (MHC) at the cell surface, changes in the dose and/or structure of the peptide component can have profound effects on T cell activation and function. In addition, the repertoire of T cells capable of responding to any given peptide is variable, but broader than a single clone. Consequently, peptide parameters that affect the interaction between T cells and peptide/MHC have been shown to select particular T cell clones for expansion and this impacts on clearance of disease. T cells with high functional avidity are selected on low doses of peptide, while low avidity T cells are favoured in high peptide concentrations. Altering the structure of the peptide ligand can also influence the selection and function of peptide-specific T cell clones. In this review, we will explore the evidence that the choice of peptide dose or the structure of the peptide are critical parameters in an effective vaccine designed to activate T cells.

No MeSH data available.