T helper epitope

Figure 3 Design of a diepitope liposomal construct. Small unilamellar liposomes (PC/PG/Chol 55/25/50 molar ratio diameter 100nm) containing 10mol% of bromo-acetyl l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine and 10mol% of the thiol-reactive lipopeptide adjuvant anchor Pam3CysAlaGly-Mal were reacted, at 25°C successively at pH 6.5, with the T-helper epitope QYI, derivatized with a C-linker at its N-terminus, followed at pH 9.0 by the B-epitope TPE derivatized with a CG linker at its N-terminus. Abbreviations PC, phosphatidylcholine PE, phosphatidylethanolamine SUV, small unilamellar vesicles. Source From Refs. 11, 20, 21.

Spielings E, Vermeulen CJ, Vogt MH, Doemer LE, et al. 2003. Identification of HLA class II restricted H-Y-specific T-helper epitope evoking CD4+ T-helper cells in H-Y-mismatched transplantation. Lancet. 362 610-615. 

The lipopeptide vaccine described in this study consists of a CD4+ helper T-cell epitope ([T]) and a B-cell epitope ([B]). These two epitopes are separated by a lysine residue (K) to which is attached the lipid moiety via two serine residues (Fig. IB). The CD4+ T-helper epitope KLIPNASLIENCTKAEL used is derived from the fusion protein of the morbillivirus canine distemper virus (34) and is recognized by T cells from BALB/c and C57BL6 mouse strains (4). The B-cell epitope is LHRH and has the sequence HWYSGLRPG. The presence of anti-LHRH antibodies can render vaccinated animals sterile. 

Ahlers ID, Belyakov IM, Thomas EK, Berzofsky IA (2001) High-affinity T helper epitope induces complementary helper and APC polarization, increased CTL, and protection against viral infection. J Clin Invest 108 1677-1685... 

Evans et al. [371] reported humoral and cellular immune responses elicited in response to a novel DNA epitope-based vaccine (AV-1955) delivered to rhesus macaques using the TriGrid electroporation device. AV-1955 generates long-term, potent anti-Ap antibodies and cellular immune responses specific to foreign T-helper epitopes but not to self-Ap. 

Although immune responses have been achieved in experimental models by the use of totally synthetic B and T cell epitope constructs, the problems of displaying multiple epitopes to cover the universe of MHC molecules and multiple serotypes are not addressed by this approach. The discovery of promiscuous T helper epitopes, that is, epitopes that elicit helper T cells in multiple strains or even in different species of animal seemed to offer a possible solution at least to part of the problem, but frequently the promiscuity is not universal and additional helper T cell epitopes are required. 

Strong cytotoxic T cell responses can also be induced when lipid is attached to the appropriate epitope. Recovery from infection with influenza virus requires the induction of an efficient cytotoxic T cell response and we have shown that the ability of a CTL epitope from the nucleoprotein of influenza virus to elicit a viral clearing responses is improved by the incorporation of a T helper epitope sequence. The clearance of virus is further augmented by the addition of 2 pdmitic acid groups (Fig.7). 

There is also considered to be a population of T suppressor cells which acts to down-regulate both T helper cells and B cells, whether through antigen-specific or idiotype-specific mechanisms. The epitopes on the lymphocyte receptor (id-iotype) recognized by the receptor on another lymphocyte (anti-idotype) can form a network of interactions through which suppression may be mediated. 

The two examples from our work we are going to describe below are the design and study of liposomal diepitope constructs combining either (i) B and T-helper (Th) peptide epitopes, which induced particularly powerful humoral responses (21) (Fig. 3) or (ii) CTL and Th epitopes, which provided a powerful antitumor vaccine (74) (Fig. 4). For the production of these constructs we have conjugated peptides that contain a cysteine residue either at the N- or C-terminus, to the surface of preformed liposomes by reaction with thiol reactive functionalized phospholipids and/or PamaCys lipopeptide anchors (Fig. 2). To that end, we have developed strategies that give, in aqueous media, high... 

Boeckler C, et al. Design of highly immunogenic liposomal constructs combining structurally independent B cell and T helper cell peptide epitopes. Eur J Immunol 1999 29 2297. 

The induction of CD4+ T helper 1 responses suggests that IRIV could provide adjuvance to the generation of HLA class I-restricted CTL responses. Thus, we addressed the capacity of IRIV to enhance the induction of CTL specific for influenza matrix (IM) 58-66 epitope and Melan-A/Mart-127-35 melanoma-associated epitope. Briefly, CD 14-cells isolated from healthy donor s peripheral blood were cocultured with autologous iDC in presence of peptide and empty IRIV or in presence of peptide alone. 

Otvos, L., Jr., Urge, L., Xiang, Z.Q., et al. (1994) Glycosylation of synthetic T helper cell epitopic peptides influences their antigenic potency and conformation in a sugar location-specific manner. Biochim. Biophys. Acta 1224, 68-76. 

Cudic, M., Ertl, H.C.J., and Otvos, LJ. (2002) Synthesis, conformation, and T-helper cell stimulation of an G-linked glycopeptide epitope containing extended carbohydrate side-chains. Bioorg. Med. Chem. 10, 3859-3870. 

Ghosh, S., Walker, J., and Jackson, D.C. (2001) Identification of canine helper T-cell epitopes from the fusion protein of canine distemper virus. Immunology 104(1), 58-66. 

The requirement of multifunctional peptide complexes is perhaps most obvious for the development of subunit peptide vaccines. Successful immunizations with peptide antigens cannot be achieved without the inclusion of a bystander T-helper cell determinant in the chemical entity (4) or in the immunizing cocktail (5). For outbred animals and humans, multiple peptide epitopes, representing determinants of more than one major histocompatibility complex (MHC) proteins, are used to overcome subunit vaccine unresponsiveness, and this also improves antigen presentation in inbred animals (6). 

As described above, peptide epitopes bound to MHC class I or II molecules are able to stimulate CD8+ and CD4+ T cells, respectively. Both CD4+ T-helper cells and CD8+ CTLs are critical to protective immunity and to vaccine efficacy. CD4+ T-helper cells play an important role in the development of memory B-cell (antibody) and memory CTL (cytotoxic T-cell) responses. CD4+ T-helper cells are also active against pathogens on their own. Therefore, CD4+ T-helper cells have been called the conductors of the immune system orchestra (14). CD8+ CTLs are able to directly kill infected target cells and thus are critical in the containment of... 

To counter the low success rate of B-cell epitope prediction, MHC class II epitopes for CD4+ T cells may be emphasized when antibody response is key in vaccine design. CD4+ T-helper cells are critical to induce the activation of B cells that produce antibodies. B-cell antigens that contain significant MHC class II epitopes may outperform B-cell antigens without cognate help. An identified T-cell epitope may sometimes contain a B-cell epitope. In addition, B-cell epitopes may colocalize near or overlap MHC class II epitopes (32, 33). 

Wiesmuller K-H, Bessler WG, Jurrg G (1992) Solid phase pep-dde syrrtlresis of lipopeptide vaccirres elicidrrg epitope-specific B-, T-helper arrd T-killer cell resporrse. hrt J Pept Proteirr Res 40 255-260. 

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