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-?(+) 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.

SUBMITTER: Popescu I 

PROVIDER: S-EPMC4239205 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature