Administration of supraphysiologic doses of recombinant growth factors to augment hematopoietic cell recovery has had a substantial impact in medical practice, with recombinant proteins now available to enhance red cell, white cell, and platelet regeneration approved for clinical use. Thus far, however, no agent able to safely expand a broad repertoire of T cells has been identified, and impaired immune reconstitution remains problematic in many clinical settings (46
). Several preclinical studies have implicated IL-7 as a primary modulator of peripheral T cell homeostasis with potent immunorestorative properties, raising the prospect that rhIL-7 may serve as a clinically effective T cell growth factor. This study demonstrates that rhIL-7 administration in humans can safely induce polyclonal T cell expansion in vivo, resulting in dramatic increases in T cell number. Although the clinical details associated with the therapy are the focus of a separate report (unpublished data), the agent was well tolerated on this trial. Mechanistically, the effect of rhIL-7 can be attributed to a combination of increased cell cycling, likely via TCR triggering to cross-reactive self-antigens, and diminished programmed cell death, which was self-limited by down-regulation of IL-7Rα in the face of continued drug administration. The rhIL-7–expanded T cells remained functional, retaining robust responsiveness to TCR triggering with even a suggestion of increased sensitivity to TCR ligation after a suboptimal stimulus, as seen in preclinical models.
rhIL-7 preferentially expanded naive CD4+
subsets, including the most naive circulating RTEs (CD4+
), consistent with the results from mouse studies (44
). The effects on CD4+
memory cells and CD4+
effectors were intermediate, whereas CD8+
effectors underwent little expansion. Notably, rhIL-7–expanded central memory CD4+
T cells, a subset that may be critically important in avoiding clonal exhaustion in the context of chronic persistent viral or tumoral antigenic exposure (47
). It is also noteworthy that rhIL-7 preferentially expanded the two subsets of T cells capable of initiating lymph node germinal center formation, the naive and central memory subsets.
Despite the clear evidence presented in this study that rhIL-7 therapy substantially increases TCR diversity by an increase in the size of the naive T cell pool, the contribution of the thymus to these rapid changes remains unclear. Preclinical studies provide evidence both for and against rhIL-7–induced augmentation of thymopoiesis (18
). In this study, we observed increases in absolute numbers of TRECs (albeit modest) and in numbers of peripheral blood phenotypic RTEs. However, we saw neither evidence for thymic enlargement nor significant correlation between age and rhIL-7 effects. Furthermore, our TREC analysis on sorted naive CD4+
cells and naive CD8+
cells shows a pronounced dilution effect of TRECs consistent with the intense proliferation in these subsets, thus arguing that the observed effect on repertoire diversity is in large part caused by decreased skewing by proliferation of RTEs. Together, these data suggest that the observed changes reflected rhIL-7–induced increases in RTE cycling, as well as trafficking of RTEs from peripheral lymphoid tissue into the bloodstream as seen in the mouse model (25
), whereas no direct effect on thymopoiesis can be demonstrated in the short time span of this study. Indeed, in clinical settings, thymic participation in immune reconstitution in adults is delayed for several months after the depleting event (30
), raising the possibility that more direct thymopoietic effects of rhIL-7, if induced, could require more chronic rhIL-7 administration. However, even if the observed rhIL-7 effects are thymic independent and reflect naive cell expansion rather than increased thymic throughput per se, the net effect of rhIL-7 therapy remains a substantial, measured, increase in TCR repertoire diversity in adult subjects, thereby reshaping their T cell pool. During the aging process, the accumulation of senescent and more oligoclonal CD8+
cells with a terminal differentiation phenotype has been associated with dysfunctional immune responses (49
). The effects of rhIL-7 on naive and central memory subsets could restore balance in T cell subsets during immunological aging and restore a T cell profile resembling that seen earlier in life. Such “antiaging” effects could prove beneficial for T cell–depleted hosts or older hosts, where the combined loss of total T cell number, naive cells, and the corollary loss of repertoire diversity appears to contribute to diminished overall immune responsiveness.
In summary, in this first clinical trial of rhIL-7 initiated in humans, and after the brief study of another National Cancer Institute–initiated trial (28
), we present evidence that rhIL-7 therapy in humans induces dramatic, polyclonal, prolonged CD4+
T cell expansion in vivo, with preferential increases in T cells bearing diverse TCR repertoire specificities. The effects are mediated primarily through increased peripheral T cell cycling and augmented cell survival. The rhIL-7–expanded T cells retain significant functional capacity, and the CD4+
T cell expansion is not accompanied by a disproportional increase in T reg cells, such as that which occurs after rhIL-2 therapy. rhIL-7 appears to be an effective T cell growth factor with “immune rejuvenating” properties that suggest it would be effective in augmenting immune reactivity in hosts with impaired immunity caused by physiological (age), iatrogenic (chemotherapy/transplantation), or pathological (HIV) lymphodepletion. In immunologically normal, as well as deficient hosts, rhIL-7's capacity to augment responses to weak antigens and to increase T cell cycling without T reg cell expansion may be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection. Future clinical studies of rhIL-7 in the context of immune-based therapies are warranted.