Primary Cytomegalovirus Phosphoprotein 65–Specific CD8+ T-Cell Responses and T-bet Levels Predict Immune Control During Early Chronic Infection in Lung Transplant Recipients

Cytomegalovirus (CMV) remains a significant opportunistic infection in solid organ transplant recipients, particularly lung transplant recipients (LTRs) [1–5]. LTRs have increased susceptibility to CMV infection, perhaps because the lung is a major reservoir for latent virus [6]. As a β-herpesvirus, CMV establishes a state of chronic infection after primary infection, with the risk of reactivation. LTRs mismatched for CMV (donor positive/recipient negative [D+R−]) have the highest risk of active CMV infection and demonstrate increased 1- and 5-year mortality [7]. Active CMV infection is a risk factor for the development of chronic allograft rejection (bronchiolitis obliterans syndrome), a major limiting factor for long-term survival in LTRs [8, 9]. Importantly, CMV viremia early after lung transplantation is strongly associated with the development of bronchiolitis obliterans syndrome in LTRs [10]. Moreover, repeated episodes of relapsing viremia in LTRs are associated with a decreased survival [11]. However, despite the impact of CMV on outcomes in LTRs, prophylaxis, monitoring, and treatment regimens vary widely among institutions and the correlates of protective immunity remain to be fully elucidated. The adaptive immune system, particularly CD8+ T cells, plays a key role in the control of acute viral infections, including CMV infection [12]. However, control of CMV during chronic infection requires ongoing effective immune surveillance to prevent viral relapse in its host [13]. Viral-specific effector CD8+ T cells exert their antiviral activities through the production of type 1 cytokines (eg, interferon γ [IFN-γ] and tumor necrosis factor α [TNF-α]) and cytolytic activity. The differentiation of effector T cells, including CD8+ T cells, is transcriptionally regulated—often by the same transcription factors that mediate their effector function [14]. The T-box transcription factor, T-bet, was first described as being critical for the development of CD4+ T-helper 1 cells in mice [15] and subsequently shown to be important in CD8+ T cells [16–18]. However, although T-bet is critical for the development of effective CD8+ T cells in animal models, little is known about its functional importance in humans. We elsewhere demonstrated the acquisition of de novo primary CMV-specific CD8+ T cell effector responses in D+R− LTRs predominated by IFN-γ production toward the structural protein of phosphoprotein 65 (pp65) [19]. We have subsequently noted relapsing CMV viremia after completion of therapy for primary infection in a subset of these D+R− LTRs during early chronic infection. We therefore hypothesized that LTRs who developed adequate CD8+ effector responses during primary infection would be protected from viral relapse during early chronic CMV infection. Herein, we report our findings of the importance of adequate induction of T-bet and its facilitation of pp65-specific effector responses in CD8+ T cells during human primary CMV infection in viral control during early chronic infection.