IL-15 transpresentation promotes both human T-cell reconstitution and T-cell-dependent antibody responses in vivo

Cytokine immunotherapies targeting T lymphocytes are attractive clinical interventions against viruses and tumors. In the mouse, the homeostasis of memory α/β CD8⁺ T cells and natural killer (NK) cells is significantly improved with increased IL-15 bioavailability. In contrast, the role of “transpresented” IL-15 on human T-cell development and homeostasis in vivo is unknown. We found that both CD8 and CD4 T cells in human immune system (HIS) mice are highly sensitive to transpresented IL-15 in vivo, with both naïve (CD62L⁺CD45RA⁺) and memory phenotype (CD62L^?CD45RO⁺) subsets being significantly increased following IL-15 “boosting.” The unexpected global improvement in human T-cell homeostasis involved enhanced proliferation and survival of both naïve and memory phenotype peripheral T cells, which potentiated B-cell responses by increasing the frequency of antigen-specific responses following immunization. Transpresented IL-15 did not modify T-cell activation patterns or alter the global T-cell receptor (TCR) repertoire diversity. Our results indicate an unexpected effect of IL-15 on human T cells in vivo, in particular on CD4⁺ T cells. As IL-15 promotes human peripheral T-cell homeostasis and increases the frequency of neutralizing antibody responses in HIS mice, IL-15 immunotherapy could be envisaged as a unique approach to improve vaccine responses in the clinical setting.In vivo studies of lymphocyte development, homeostasis, and immune responses upon infection, antigenic challenge, or following vaccination have been largely characterized in mice. Although this line of experimentation is valuable, 60 million years of evolution have generated important differences between murine and human immune systems, and therefore some of the knowledge derived from mouse models may not be directly applicable to humans. An intermediate between murine and human in vivo studies exists in the form of human immune system (HIS) mice. A recently developed HIS mouse model involves engraftment of newborn BALB/c Rag2^?/? γ_c^?/? mice with human hematopoietic stem cells (HSCs) from fetal liver or cord blood, which generates human innate and adaptive lymphocytes and dendritic cell subsets required for immune responses (1–3). HIS mice are proving to be a very powerful biotechnology, and although they are successfully used to model human hematopoiesis, their capacity for studying human immune responses is suboptimal (2). This is likely due to perturbed homeostasis of human T cells in BALB/c Rag2^?/? γ_c^?/? HIS mice, as these cells exhibit an abnormally high turnover rate and fail to accumulate (1–5). Not surprisingly, many current efforts are focused on improving human T-cell reconstitution and homeostasis in HIS mice with the ultimate goal of inducing robust and consistent human immune responses in vivo.T-cell homeostasis comprises T-cell generation in the thymus, export to the periphery, maintenance of the peripheral naïve T-cell pool, and regulation of activated effector and memory T-cell compartments (6). Several signals have been implicated in controlling T-cell homeostasis, including those emanating from the T-cell receptor (TCR) following interactions with self-peptide + major histocompatibility complex (pMHC) and those induced by growth factors, including cytokines (6). The common cytokine receptor gamma chain (γ_c) family of cytokines (which comprises IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) in particular have been demonstrated to play a role in T-cell homeostasis in mammals (7). Humans and mice possessing mutations in genes encoding the γ_c, Jak3 (both critical for signal transduction following binding γ_c cytokines) or the alpha chain of the IL-7 receptor (IL-7Rα), display a severe block in T-cell development and resulting severe combined immunodeficiency (8, 9). The γ_c-dependent cytokine IL-15 is unusual because its bioactive form is a functional complex associated with the IL-15Rα chain. Thus, cells expressing IL-15 such as monocytes, dendritic cells, and stromal cells must also coexpress the IL-15Rα to “transpresent” IL-15 to IL-15–responsive cells (that express the IL-2Rβ/γ_c complex). Accordingly, both IL-15 and IL-15Rα are up-regulated on myeloid cells following inflammation, thereby increasing IL-15 bioavalability (10–12).We demonstrated that transpresented murine IL-15 inefficiently triggered human natural killer (NK) cells in vitro and in vivo providing an explanation for the poor human NK cell reconstitution in BALB/c Rag2^?/? γ_c^?/? HIS mice (3). Exogenous administration of a potent human IL-15R agonist (referred to as RLI, consisting of human IL-15 covalently linked to an extended human IL-15Rα “sushi” domain thus mimicking IL-15 transpresentation) (13–15) was sufficient to restore human NK cell development in HIS mice (3). Whereas memory CD8⁺ T cells in mice are highly responsive to exogenous IL-15 (6, 11–14), naïve CD4⁺ and CD8⁺ T cells are not thought to require IL-15 for normal homeostasis (6, 11–14). However, in vivo effects of human IL-15 on human T cells have not been studied, and it remained possible that the poor reactivity of human T cells to mouse IL-15 might also contribute to the low human T-cell reconstitution in the HIS mouse model. Here we show that human IL-15 transpresentation increases human T-cell reconstitution and the frequency of T-cell–dependent antibody responses in HIS mice. These studies provide a first preclinical trial of transpresented human IL-15 on human T cells in vivo and indicate that increased IL-15 bioavailability globally boosts human naïve and memory T-cell homeostasis in this humanized mouse model. Our findings offer a unique approach to study human T-cell immune responses in vivo and suggest that IL-15 immunotherapy may be useful to promote global T-cell reconstitution in humans.