High-affinity T helper epitope induces complementary helper and APC polarization, increased CTL, and protection against viral infection
Jeffrey D. Ahlers, … , Elaine K. Thomas, Jay A. Berzofsky
Jeffrey D. Ahlers, … , Elaine K. Thomas, Jay A. Berzofsky
Published December 1, 2001
Citation Information: J Clin Invest. 2001;108(11):1677-1685. https://doi.org/10.1172/JCI13463.
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Article

High-affinity T helper epitope induces complementary helper and APC polarization, increased CTL, and protection against viral infection

Abstract

Natural viral proteins do not always make optimal vaccines. We have found that sequence modification to increase epitope affinity for class II MHC molecules (epitope enhancement) can improve immunogenicity. Here we show first that a higher-affinity helper epitope-enhanced HIV vaccine not only induces more cytotoxic T lymphocytes (CTLs), but also skews helper cells toward Th1 cytokine production and protects against HIV-1 recombinant vaccinia viral challenge. Furthermore, we elucidate a novel mechanism in which the higher-affinity vaccine induces dramatically more effective helper cells with a higher level of CD40L per helper cell and more positive cells, which in turn more effectively conditions dendritic cells (DCs) for CTL activation in a second culture. The improved helper cells also induce much greater IL-12 production by DCs, accounting for the reciprocal T helper polarization to Th1, and increase costimulatory molecule expression. Thus, increasing affinity for class II MHC results in a complementary interaction in which T helper and antigen-presenting cells polarize each other, as well as increase CTL, and provide greater vaccine efficacy against viral infection.

Authors

Jeffrey D. Ahlers, Igor M. Belyakov, Elaine K. Thomas, Jay A. Berzofsky

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Differential expression of costimulatory molecules. Eight-day A.AL DC cu...
Differential expression of costimulatory molecules. Eight-day A.AL DC cultures (5 × 105 cells/well of 96-well round-bottom plate) grown with GM-CSF (10 ng/ml) were conditioned for 20 hours by incubation with 5 × 104 CD4+ Th cells and 0.5 μM peptide T1 or T1(A). (a) Gated class II+ cells were examined for expression of CD40 and costimulatory molecules B7-1 and B7-2 after stimulation with T1(A) (solid heavy line) compared with T1 (light line). DC cultures incubated with the Th cell without peptide are shown as the shaded area and are similar to cultures incubated without Th cells (not shown). (b) Eight-day BALB.A10 DCs were conditioned similarly for 36 hours. Gated CD11c+ shown in the first panel as the shaded area compared with PE-isotype control (dashed line) were examined for costimulatory molecules B7-1, B7-2, ICAM, and CD44H — DCs conditioned with Th cells stimulated with T1(A) (solid heavy line) versus T1 (light line). The shaded area represents DC cultures incubated with resting Th cells not stimulated with peptide. CD40 was maximally expressed under all culture conditions in this experiment. For B7-1 and 2, T1 and T1(A) are shown in separate panels for clarity. Similar results were observed in five additional experiments.