Universally immunogenic T cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells

Abstract

To understand the effect of human MHC class II polymorphism on antigen recognition, we analyzed the memory T cell response to three tetanus toxin epitopes defined by three short synthetic peptides (p2, p4 and p30). We found that p2 and p30 are universally immunogenic, since they are recognized by all primed donors, irrespective of their MHC haplotypes. The analysis of specific clones indicates that both peptides are very promiscuous in their capacity to bind to class II. p30 can be recognized in association with DRw11(5), 7, 9 and with DPw2 and DPw4, while p2 can be recognized in association with DR1, DRw15(2), DRw18 (3), DR4Dw4, DRw11(5), DRw13(w6), DR7, DRw8, DR9, DRw52a and DRw52b. On the contrary, the third peptide, p4, can be recognized by only half of the donors in association with only DRw52a and DRw52c. Analysis of truncated peptides shows that p30 contains three distinct epitopes, each recognized in association with different class II molecules. Therefore, the restriction specificity is already set at the level of the peptide-MHC complex and, in all cases, T cells discriminate p30 bound to different class II molecules. On the contrary, p2 contains only one epitope, which is recognized in association with all DR molecules. In this case we found two different restriction patterns. Some clones are monogamous, since they recognize the peptide in association with one DR allele, while others are promiscuous, since they recognize by peptide in association with several different DR molecules. Thus, in this case, the restriction specificity is also set at the level of the T cell receptor. We suggest that both the promiscuous binding of peptides and the promiscuous recognition by T cells are dependent on the particular structure of the DR molecules, having a monomorphic alpha chain associated with a polymorphic beta chain.

Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

“…Briefly, the N-terminus of the immunodominant B cell epitope of Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] was synthesized in tandem with a promiscuous foreign T cell epitope, PADRE (aK-Cha-VAAWTLKAAa, where "a" is D alanine and "Cha" is L-cyclohexylalanine) as Multiple Antigenic Peptides (MAP), which contain a core matrix of 4 branching lysines [42,43] to generate PADRE-Aβ 1-15 -MAP molecules (Invitrogen Inc., CA).…”

“…In addition to the magnitude of humoral immune responses we also analyzed the isotype of anti-Aβ 42 antibodies, since this characteristic has previously been used as an indirect measure of the contribution of Th1 (IgG2a) and Th2 (IgG1) cytokines to the immune response [44][45][46]. Three to six injections with PADRE-Aβ 1-15 -MAP epitope vaccine formulated in Alum generated predominantly IgG1 anti-Aβ antibodies in BALB/c mice (Fig.…”

“…This AN-1792 clinical trial was halted due to the development of meningoencephalitis in a small proportion of the subjects [21][22][23][24][25][26], but follow up studies have demonstrated that strong anti-Aβ antibody responses specific to the linear Aβ [1][2][3][4][5][6][7][8] peptide [27] in some patients reduced AD pathology and diminished the cognitive decline associated with the disease [24,[27][28][29][30][31][32][33]. These data along with preclinical studies demonstrated that anti-Aβ antibodies directed to N-terminal region of Aβ 42 are effective in clearance of amyloid plaques [16,34,35]. On the contrary, the strong autoreactive Th1-type response specific to Aβ is thought to underlie the development of meningoencephalitis observed in the AN-1792 trial [30,31,33].…”

Peptide immunization in humans: a combined CD8+/CD4+ T cell-targeted vaccine restimulates the memory CD4 T cell response but fails to induce cytotoxic T lymphocytes (CTL)

“…In order to guarantee appropriate help for the growth of peptide-specific CTL, we used as adjuvant the 'p30' peptide derived from TT (tetanus toxin/tetanus toxoid; [21] ). In the Caucasian population, this epitope should be recognized by most individuals, as it represents an ubiquitous T helper epitope in the TT protein [22,23]. Moreover, the human population is widely vaccinated with TT, and therefore coimmunization with the p30 epitope from this common 'recall' antigen should be suitable to stimulate a part of the TT-specific T helper memory immune response in most vaccinated individuals.…”

Lipopeptide‐based melanoma cancer vaccine induced a strong MART‐27‐35‐cytotoxic T lymphocyte response in a preclinal study

“…The TT830-843 peptide, derived from tetanus toxoid, was chosen as a source of T cell help because of its promiscuous binding to human MHC class II antigens and its promiscuous recognition by T cells. 20 Lipopeptides constructs, differing in nature of spacer sequences and number of lipid chains, were synthesized. In the various lipopeptide formulations tested, lipid tails were linked to the universal tetanus toxoid (TT 830-843) epitope HTL that was itself linked to the HLA-A2 restricted MART 27-35 CTL epitope.…”