IL-7 receptor α blockade, an off-switch for autoreactive T cells

T cells that escaped immune regulation and subsequently target insulin-producing β-cells are thought to be a major contributor of type 1 diabetes (T1D) development (1). Thus, harnessing autoreactive effector T cells appears to be a central requirement for novel therapeutic approaches that are urgently needed. The studies by Lee et al. (2) and Penaranda et al. (3) in PNAS demonstrate that blockade of IL-7 signaling can revert recent onset diabetes by fostering the inhibitory programmed cell death 1 (PD-1) protein on diabetogenic T cells, thereby limiting their autoaggressive potential.

Fig. 1.

IL-7 and PD-1 have antagonistic effects in the regulation of immune responses. PD-1 expression is diminished in the presence of high IL-7 levels, causing improved T cell-mediated immune control of tumor and viruses (7, 8) but enhancing the risk for development of autoimmune diseases (9, 10). In contrast, blockade of IL-7 signaling increases PD-1 expression, thus protecting the host from autoimmune diseases (2, 3). Whether or not this setting bears the risk for development of opportunistic infections or cancer requires careful investigation.

The pleiotropic cytokine IL-7 is a central regulator of T-cell homeostasis in mice and humans (4). It is known to regulate T-cell memory formation as well as recall responses (5), and expression of the IL-7 receptor-α (IL-7Rα) chain is a key feature of memory precursor T cells (6). Recently, the therapeutic implications of IL-7 modulation were demonstrated in a tumor model and a model of protracted viral infection. In both cases, therapeutic administration of recombinant IL-7 enhanced the antigen-specific T-cell responses by amplifying survival and effector mechanisms and counteracting several inhibitory pathways, such as PD-1 (7, 8). However, IL-7 has the unfortunate ability to promote the emergence of autoreactive T cells, and thus can be associated with the development of autoimmune diseases (9, 10). The importance of IL-7 in the development of autoimmune disorders is further underlined by observations from genome-wide association studies that identified genetic variations of the IL-7Rα chain as risk factors for the development of T1D and multiple sclerosis (11, 12). Lee et al. (2) and Penaranda et al. (3) have now determined the therapeutic implications of these findings in a murine model of immune-mediated diabetes, the nonobese diabetic (NOD) mouse.

The NOD mouse constitutes an animal model of T1D that shares several key features with human disease, such as genetic predisposition and spontaneous disease onset (13). The authors demonstrate that administration of an antibody that blocks the IL-7Rα chain prevented diabetes development and reverted recent onset disease in this model. Notably, the restoration of euglycemia after disease manifestation is a goal that is rarely met. Indeed, although the list of therapeutic interventions that can prevent the development of T1D in mouse models is long and constantly growing, such interventions that can revert diabetes after onset of the disease are rare, even in the mouse (14). From a translational standpoint, however, it is crucial to have therapeutic approaches available that are powerful enough to cure or ameliorate diabetes after diagnosis, because this is the situation in which the vast majority of diabetic patients are diagnosed.

Because genetic IL-7R deficiency profoundly reduces the number of circulating T cells (15), the authors analyze whether transient therapeutic blockade would have a similar effect. They demonstrate that different antibody clones differentially affected overall T-cell numbers and, strikingly, that reduction of circulating T cells is not a requirement for the antidiabetic efficacy (2). Moreover, both studies are in agreement that autoaggressive T cells are silenced rather than depleted. Indeed, although T cells from control animals that were transferred into NOD/SCID mice induced diabetes in their host, T cells derived from anti–IL-7Rα–treated mice transferred diabetes either in a delayed fashion or failed entirely, demonstrating the attenuated diabetogenicity of these cells. The functional differences were also accompanied by phenotypic alterations. The authors show that IL-7Rα blockade induced PD-1 expression on T cells, an inhibitory receptor that potently restrains effector functions (16), suggesting a link between IL-7 signaling and PD-1 expression. The biological significance of PD-1 expression following IL-7Rα blockade is subsequently demonstrated by PD-1 blockade experiments. Both groups elegantly show that blockade of the PD-1 pathway largely abrogates the protective effect of IL-7Rα blockade (2, 3). Indeed, mice that recovered from diabetes following IL-7Rα blockade rapidly developed hyperglycemia in response to PD-1 blockade (2). These findings are in agreement with previous reports that pointed toward an important role for PD-1 in protection from diabetes (17, 18).

Another factor that might contribute to the observed protection from diabetes in anti–IL-7Rα–treated mice is the presence of regulatory T cells (Tregs). Although the suppressive activity of Tregs does not seem to be affected by IL-7Rα blockade, both studies are in agreement that the balance between effector cells and Tregs shifts toward Tregs in anti–IL-7Rα–treated mice. However, the degree to which Treg-mediated immune regulation contributes to disease protection remains unclear.

Both reports add significant information to an emerging picture in which IL-7 and PD-1 act as antagonists in the regulation of antigen-specific T-cell responses. Indeed, although the molecular connection remains to be identified, the authors clearly demonstrate that IL-7 reduces

Blockade of the PD-1 pathway largely abrogates the protective effect of IL-7Rα blockade.

PD-1 expression and blockade of IL-7Rα promotes PD-1 expression, providing evidence for a strong link between the IL-7 and PD-1 pathways. Although this connection bears great therapeutic potential, it also carries undeniable risks. Just as IL-7 treatment for chronic viral infections bears the risk for developing autoimmune diseases by thwarting immune regulation (8–10), blockade of the IL-7R might increase the susceptibility for certain infections or even cancer in humans. Therefore, the degree to which IL-7Rα actually induces immunosuppression, if at all, needs to be carefully investigated in the future. Given the young age at which T1D is often diagnosed, generalized immunosuppression, as an adverse drug reaction, constitutes a major limitation for many potentially powerful drugs. However, there might be a way to overcome this caveat in part. Indeed, certain combination therapies in T1D are not only capable of reverting disease in animal models but bear the potential to significantly reduce drug toxicity (14). It has been shown that the dose of a systemic immunomodulator, such as anti-CD3, can be greatly reduced when combined with an antigen-specific approach (19, 20). Thus, when crafting a cure for T1D, we should embrace various techniques, and the reports by Lee et al. (2) and Penaranda et al. (3) have added an interesting device to the toolbox to do so.