T-bet:Eomes Balance, Effector Function, and Proliferation of Cytomegalovirus-Specific CD8+ T Cells during Primary Infection Differentiates the Capacity for Durable Immune Control

Abstract

CMV remains an important opportunistic pathogen in solid organ transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor+/recipient−; D+R−) are at high-risk for active CMV infection and increased mortality, however the immune correlates of viral control remain incompletely understood. We prospectively studied 23 D+R− LTRs during primary CMV infection to determine whether acute CD8+ T cell parameters differentiated the capacity for viral control in early chronic infection. T-box transcription factors expression patterns of T-bet > Eomesodermin (Eomes) differentiated LTR controllers from viremic relapsers and reciprocally correlated with granzyme B loading, and CMV phosphoprotein 65 (pp65)–specific CD8+IFN-γ+ and CD107a+ frequencies. LTR relapsers demonstrated reduced CD8+Ki67+ cells ex vivo and substantially impaired CD8+pp65-specific in vitro proliferative responses at 6 d, with concomitantly lower pp65-specific CD4+IL-2+ frequencies, as compared with LTR controllers. However, CMV-specific in vitro proliferative responses could be significantly rescued, most effectively with pp65 Ag and exogenous IL-2, resulting in an increased T-bet:Eomes balance, and enhanced effector function. Using class I CMV tetramers, we observed similar frequencies between relapsers and controllers, although reduced T-bet:Eomes balance in tetramer+ cells from relapsers, along with impaired CD8+ effector responses to tetramer-peptide restimulation. Taken together, these data show impaired CMV-specific CD8+ effector responses is not for complete lack of CMV-specific cells but rather underscores the importance of the T-bet:Eomes balance, with CMV-specific proliferation a key factor driving early T-bet expression and effector function in CD8+ T cells during primary infection and differentiating the capacity of high-risk LTRs to establish immune control during early chronic infection.