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Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool
Fraia Melchionda, … , Yutaka Tagaya, Crystal L. Mackall
Fraia Melchionda, … , Yutaka Tagaya, Crystal L. Mackall
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1177-1187. https://doi.org/10.1172/JCI23134.
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Article Vaccines

Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool

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Abstract

Current models of T cell memory implicate a critical role for IL-7 in the effector-to-memory transition, raising the possibility that IL-7 therapy might enhance vaccine responses. IL-7 has not been studied, to our knowledge, before now for adjuvant activity. We administered recombinant human IL-7 (rhIL-7) to mice during immunization against the male antigen HY and compared these results with those obtained from mice immunized with rhIL-2 and rhIL-15. Administration of rhIL-7 or rhIL-15, but not rhIL-2, increased effector cells directed against these dominant antigens and dramatically enhanced CD8+ effectors to subdominant antigens. The mechanisms by which the cytokines augmented effector pool generation were multifactorial and included rhIL-7–mediated costimulation and rhIL-15–mediated augmentation of the proliferative burst. The contraction phase of the antigen-specific response was exaggerated in cytokine-treated mice; however, CD8+ memory pools in rhIL-7– or rhIL-15–treated groups demonstrated superior long-term survival resulting in quantitative advantages that remained long after the cytokines were discontinued, as demonstrated by improved survival after challenge with an HY-expressing tumor undertaken several weeks after cytokine cessation. These results confirm the adjuvant activity of rhIL-15 and demonstrate that rhIL-7 also serves as a potent vaccine adjuvant that broadens immunity by augmenting responses to subdominant antigens and improving the survival of the CD8+ T cell memory pool.

Authors

Fraia Melchionda, Terry J. Fry, Matthew J. Milliron, Melissa A. McKirdy, Yutaka Tagaya, Crystal L. Mackall

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Figure 1

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The γc cytokines expand splenic T cell populations. (A–C) C57BL/6 mice r...
The γc cytokines expand splenic T cell populations. (A–C) C57BL/6 mice received rhIL-2 (n = 9), rhIL-7 (n = 9), rhIL-15 (n = 9), or carrier alone (n = 9) daily i.p. from day 0 (d 0) to day 27 as described in Methods. Data from 1 representative experiment are shown; results were confirmed in 3 separate experiments. (A) Serum levels of hIL-7 (left panel) and hIL-15 (right panel) were measured 24 hours after injection. Levels were stable throughout therapy and returned to baseline upon cessation of therapy. (B) All cytokine groups showed significant increases in splenocyte number on day 28. (C) CD8+ (P < 0.0001) and CD4+ (P < 0.0001) splenocyte populations were expanded equally (1.5–to 2.0–fold) by rhIL-7, with persistent CD4+ expansion for 14 days despite serum clearance of the cytokine. CD8+ cell populations were expanded (4–fold; P < 0.0001) but CD4+ T cell numbers were reduced by 30% by rhIL-15. Increases of less than 2-fold were induced by rhIL-2 in CD8+ (P < 0.0001) and CD4+ (P = 0.008) splenocytes.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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