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Editorial: Hijacking the IL‐7/IL‐7R system in HIV infection

IL-7 is a cytokine that regulates the homeostatic balance of T cells, impacting on their development, function, proliferation, and survival [1]. To mediate signaling, IL-7 binds the IL-7R, a dimeric complex composed of a highaffinity chain (CD127) and the common chain (CD132), which is shared with several other cytokine receptors, namely IL-2, IL-4, IL-9, IL-15, and IL-21 [2]. The presence of CD127 on the cell surface appears to be the primary determinant of responsiveness to IL-7 [2]. The role of the IL-7/IL-7R signaling complex becomes particularly important in the setting of a substantial loss of T cells when the remaining cells initiate a homeostatic response to repopulate the depleted compartment. The manuscript by Vranjkovic and colleagues [3], published in this issue, reports studies aimed at determining the efficiency of the IL-7/IL-7R signaling in the setting of HIV infection. Several studies have shown that HIV infection is consistently associated with a decrease fraction of CD8 T cells expressing CD127 [4, 5]. A reduced fraction of CD127 cells has been also documented for CD4 T lymphocytes of HIV-infected individuals, even if less dramatic than for CD8 T cells. Perturbation in the expression of IL-7R may have a prominent, pathogenic role in the setting of HIV infection, where CD4 T cells are severely depleted in blood and tissues during the course of the infection, and CD4 and CD8 T cells are less functional and more susceptible to activation-induced cell death. The IL-7 regulatory pathway is activated during HIV-induced lymphopenia (Fig. 1), as indicated by the increased levels of IL-7 observed during HIV infection [6], but it is not sufficient to maintain T cell homeostasis, as the natural history of HIV infection is invariably characterized by a progressive CD4 T cell decline. Interestingly, a recent study in rodents suggests that by signaling in IL-7R DCs, the increased availability of IL-7 during lymphopenia may paradoxically limit the homeostatic proliferation of CD4 T cells [7]. Hence, IL-7 regulation of T cell homeostasis is a complex phenomenon, and a better elucidation of the IL-7/IL-7R pathways is of critical importance in understanding the regulation of T cell homeostasis in HIV-infected patients. Supporting the importance of IL-7R expression in AIDS pathogenesis is the fact that, in HIVinfected individuals, the levels of CD8 CD127 T cells correlate directly with markers of disease progression (i.e., plasma viremia and CD4 T cell depletion), as well as with the overall levels of immune system activation [5]. In addition, the levels of CD8 CD127 represent the main determinant of the extent of CD4 T cell gains after HAART [8]. Although several studies confirmed the reduced CD127 expression on CD8 T cells as a novel feature of the HIV-associated immune perturbation, it is still unclear if the remaining CD8 CD127 T cells are functional, as in healthy controls, or if even these phenotypically “normal” T cells are actually defective in their response to IL-7. The manuscript by Vranjkovic and colleagues [3] reports studies aimed at addressing this question. This is an important question, particularly considering that IL-7 has elicited significant interest as a potential immunotherapy for HIVinfected individuals, and it has been introduced recently in two clinical trials in HAART-treated, HIV-infected individuals, with the goal of increasing the number and function of CD4 and CD8 T cells [9, 10]. Encouragingly, these studies showed a significant increase in the numbers of circulating CD4 and CD8 T cells with a naive and central memory phenotype in IL-7treated patients. To determine their ability to signal through IL-7R, Vranjkovic and colleagues [3] purified CD8 CD127 T cells from healthy controls and HIVinfected individuals, naive or HAARTexperienced, and compared their responsiveness with IL-7 stimulation. The main finding of the study is that HIV infection is associated with a defective, IL-7-dependent activation of STAT5, the prominent and best-characterized molecule in the IL-7/IL-7R signaling cascade, on CD8 CD127 T cells. Specifically, a lower percentage of cells expressing the p-STAT5 and a lower amount of p-STAT5 in the positive cells (as determined by mean fluorescent intensity) were found in untreated, HIVinfected individuals. Furthermore, the defective IL-7/IL-7R signaling resulted in impaired proliferation of