Disarming the Old Foe. Restoring T-Cell Immune Function with mTor-Inhibitors to Tackle Cytomegalovirus Infection

Cytomegalovirus (CMV) infection remains a main opportunistic infection after solid organ transplantation (SOT), challenging both patient and graft outcomes.¹ Yet, despite important advances in the field in the last decades with more precise molecular tools to detect viral replication and effective antiviral therapies preventing and controlling viral spread, the clinical management of CMV infection is still highly erratic and often based in reactive empirical changes of maintenance immunosuppression to optimize the global immunosuppressive burden of transplanted patients.

In recent years, increasing attention has been dedicated to this field, to better understand the intricate immune mechanisms of CMV infection. Although it is well known that the control of CMV infection requires an orchestrated role of both innate and adaptive immune cells,² the spotlight has focused on the T-cell immune compartment, with clinical observations highlighting the relevance of CMV-specific memory/effector CD4+ and CD8+ αβ T cells preventing as well as controlling CMV replication and spread in SOT recipients,^3,4 a biologic setting in which Vδ2neg γδ T cells seem to also be involved.⁵ However, not all patients with prior exposure to CMV seem to be capable of efficiently control CMV infection, thus suggesting that dysfunctional antigen-specific memory T cells may be present in some patients. In fact, in certain clinical settings such as after uncontrolled chronic viral infections and within tumor microenvironments,⁶ unlike naïve T cells, effector memory T cells acquire an exhausted immune profile, which is predominantly characterized by high expression of inhibitor receptors and transcriptional factors ultimately reducing their ability to release proinflammatory cytokines and to proliferate (Figure 1).

Figure 1.: Immunomodulation of mTor-inhibitors promoting the restoration of a functional immune profile on memory CD8+ αβ T cells and Vδ2neg γδ T cells enabling CMV viral control. CMV, cytomegalovirus; mTor-I, mammalian target of rapamycin inhibitors; NK T cells, natural killer cells; R+, CMV IgG serological positive transplant recipients.

Of note, among the different immunosuppressive agents used after SOT, inhibitors of mammalian target of rapamycin (mTor-i), both sirolimus and everolimus, have been associated with a significant reduced incidence of CMV infection among intermediate risk seropositive transplant recipients.⁷ The most documented explanation is sustained by a direct antiviral mechanism through the inhibition of the PI3K-Akt-mTOR pathway including the mTOR complex 1 (mTorC1) downstream effectors (S6rp) and the translation factor 4E-BP-1 that avoids viral translation into the cell host.⁸ Nevertheless, mTor-i have also been shown to booster antitumor T-cell immune responses and decrease the tumor growth⁹ as well as to reduce the incidence of infections and enhance T-cell responses after influenza vaccination among elderly individuals by reducing the proportion of exhausted PD1+ memory T cells.¹⁰ Altogether, these data underscore the hypothesis that the reduction of CMV infection rates in SOT receiving mTor-i may not only be driven by a direct antiviral effect but also by an immunomodulatory capacity improving CMV-specific T-cell function and viability.

In the current issue of the journal, Kaminsky and colleagues¹¹ report an elegant and thorough evaluation of the pleiotropic effects of the mTor-i Everolimus (EVL), on the function and phenotype of both CMV-specific CD8+ αβ T cells and Vδ2neg γδ T cells associated with CMV replication in CMV seropositive kidney transplant patients. The authors performed a number of in vitro studies, dissecting the role of EVL, on memory T cell activation and function as compared with patients not receiving this drug. A first important observation of the study describes that prior to transplantation kidney transplant candidates with a predominant dysfunctional phenotype on both Vδ2neg γδ T cells and CD8+ αβ T-cells, defined as high expression of inhibitory receptors such as PD-1, LAG3, TIM3, CD161, and CD85j, were found to more frequently develop CMV infection after transplantation. In vitro studies confirmed the profound dysfunctional profile of effector T cells showing high expression of PD-1 as well as the transcription factor EOMES, but low levels of Hobit for the same Tbet level. Of note, the sole evaluation of PD-1 and CD85j, expressed on both CMV-specific CD8+ αβ T cells and Vδ2neg γδ T cells prior to transplantation could accurately stratify patients at different risk of posttransplant CMV infection. Most interestingly, they subsequently show the recovery of a functional immune phenotype on these cells defined by a decrease in inhibitory receptors in patients receiving EVL, a feature that was linked to an enhanced functional capacity to release proinflammatory cytokines in response to a CMV stimuli in vitro. Remarkably, these patients did not only develop lower incidence and severity of CMV infection but also showed a better replication control during the course of CMV infection. Of note, they further demonstrate in vitro that such effect was directly associated with EVL therapy and not with MPA withdrawal. Finally, the authors also showed that such immune recovery was accompanied by a clear TCR signaling improvement, which may ultimately account for the proper antiviral immune response to clear the virus.

The authors must be congratulated for this important study that moves the field forward by providing new insights on the immune biology of CMV infection in the context of SOT. These observations are relevant because they describe a new biologic feature of the antiviral immune response facilitating CMV infection in SOT recipients, a finding that may be extended to other opportunistic viral infections. Although these data add on previous works underscoring the relevance of quantifying CMV-specific T-cell immune responses to better stratify the risk of CMV infection, it further refines this knowledge and describes the basis of the poor effector antiviral immune function in some seropositive SOT patients and how such dysfunctional immune state may be reversed by the use of mTor-i. Most importantly, the study paves the way for future prospective, interventional studies to demonstrate the value of mTor-i to prevent or even treat CMV replication in a biomarker-guided manner by modulating the antiviral immune response rather than using a generalized and unnecessary antiviral therapy with associated toxic adverse events.

Nevertheless, there are important questions that remain to be dilucidated; yet the relative involvement of both CD8+ αβ T cells and Vδ2neg γδ T cells, driving immune protection against CMV infection, as well as whether such a dysfunctional immune signature may be also responsible for those difficult-to-treat CMV infections challenging patient and graft outcomes.

In summary, after more than two decades using mTor-i in SOT to prevent allograft rejection, the novel immunomodulatory effects of these drugs boostering antiviral memory/effector immune responses may allow repositioning their use in transplantation and ultimately lead to a new era in which CMV infection will no longer represent a major danger in SOT patients.

Disclosures

O. Bestard reports Patents and Inventions: Oxford Immunotec; and Scientific Advisor or Membership: Associate Editor of Transplant International and Frontiers in Immunology journals. Remaining author has nothing to disclose.

Funding

The authors acknowledge receiving funding from Instituto de Salud Carlos III grant PI16/01321, the REDINREN (Spanish Renal research network) and the European Union’s Horizon 2020 research and innovation programme under grant 754995.