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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Blocking both B7-1 and B7-2 on DCs inhibits the CTL response. BALB.A10 D...
Blocking both B7-1 and B7-2 on DCs inhibits the CTL response. BALB.A10 DC cultures (2.5 × 10 6) conditioned for 24 hours with Th cells and peptide, T1, or T1(A) (0.5 μM), or no peptide, were depleted of CD4+ cells, pulsed for 1 hour with the CTL epitope P18IIIB (0.5 μM), irradiated, and added to 5 × 106 negatively selected splenic CD8+ cells from BALB.A10 mice primed 1 month earlier subcutaneously with PCLUS 3-18IIIB (20 nmol). (a) DCs conditioned with Th cell and T1(A) elicited higher levels of CTL than DCs conditioned with either Th cells and T1 or no peptide, or overnight treatment with trimeric murine CD40L (3 μg/ml). Lytic activity was determined on day 7 in a 5-hour 51Cr assay on 0.5 μM P18IIIB-pulsed P815 target cells (E/T = 10:1). (b) DCs were conditioned with Th cells and T1(A) (0.5 μM) for 24 hours and CD4+ cells removed. Cells were pulsed for 1.5 hours with P18IIIB, irradiated, and used to stimulate immune CD8+ cells. Anti–B7-1/B7-2 (15 μg/ml each), anti–IL-12 (15 μg/ml), anti-CCR5 (10 μg/ml), or anti-41BBL (10 μg/ml) were added to pulsed DCs at the initiation of CTL culture and on day 3. Similar results were obtained in two additional experiments.