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. IntroductionImmunization is the central therapeutic maneuver that immunology has to offer. Whereas vaccines designed to induce B cell memory to prevent acute infections are highly effective, vaccines that aim to induce and maintain high level T cell responses for chronic infections such as HIV and cancer have had limited success (1, 2). The challenges of immunization for cancer and chronic infection are manifold and include ongoing mutation of target antigens (3), anergy and/or suppression due to chronic antigen overload (4), and the large size of the target pool, which requires dramatic T cell population expansion for therapeutic benefit (5). Thus, new approaches for increasing the size and broadening the diversity of effector and memory pools generated after immunization are needed to improve the prospect of generating an effective preventative vaccine for HIV and to enhance the effectiveness of immunotherapy for chronic infections and cancer. Extensive progress has been made in understanding the mechanisms regulating effector-to-memory cell transition and in identifying factors that maintain the memory T cell pool. Currently, paradigms hold that memory CD8 + T cells represent highly "fit" cells derived from the effector T cell population (6-9), thus leading to the prediction that therapies which augment T cell effector pools will also augment T cell memory pools (10, 11). Several recent insights into the biology of IL-7 suggest that IL-7 might serve as an effective vaccine adjuvant.

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. IntroductionImmunization is the central therapeutic maneuver that immunology has to offer. Whereas vaccines designed to induce B cell memory to prevent acute infections are highly effective, vaccines that aim to induce and maintain high level T cell responses for chronic infections such as HIV and cancer have had limited success (1, 2). The challenges of immunization for cancer and chronic infection are manifold and include ongoing mutation of target antigens (3), anergy and/or suppression due to chronic antigen overload (4), and the large size of the target pool, which requires dramatic T cell population expansion for therapeutic benefit (5). Thus, new approaches for increasing the size and broadening the diversity of effector and memory pools generated after immunization are needed to improve the prospect of generating an effective preventative vaccine for HIV and to enhance the effectiveness of immunotherapy for chronic infections and cancer. Extensive progress has been made in understanding the mechanisms regulating effector-to-memory cell transition and in identifying factors that maintain the memory T cell pool. Currently, paradigms hold that memory CD8 + T cells represent highly "fit" cells derived from the effector T cell population (6-9), thus leading to the prediction that therapies which augment T cell effector pools will also augment T cell memory pools (10, 11). Several recent insights into the biology of IL-7 suggest that IL-7 might serve as an effective vaccine adjuvant.

Despite recent progress in our understanding of the biology of T-cell homeostasis, clinically available therapies to substantially improve immune reconstitution in patients sustaining T-cell depletion are lacking. T cells are regenerated via a dynamic interplay between thymopoiesis and thymicindependent homeostatic peripheral expansion (HPE). Using athymic mice subjected to T-cell depletion, we observed that HPE is critically dependent on dendritic cells (DCs) for presentation of antigen, raising the possibility that the availability of DCs might be limiting in vivo for HPE to occur efficiently. Indeed, flt3 ligand (flt3L) treatment of athymic mice subjected to T-cell depletion (without DC depletion) substantially enhanced HPE and improved immune competence. Following bone marrow transplantation (BMT) in athymic hosts, both dendritic cells and T cells were profoundly depleted and flt3L therapy restored DC numbers and enhanced HPE. In addition, thymus-bearing BMT recipients treated with flt3L regenerated increased numbers of thymic-dependent progeny with increased numbers of T-cell receptor excision circle (TREC)-positive T cells, indicating increased thymopoiesis. Therefore, flt3L is a potent immunorestorative agent that enhances both thymic-dependent and thymic-independent pathways of T-cell regeneration. (Blood.