IL-12-Dependent Cytomegalovirus-Specific CD4+ T Cell Proliferation, T-bet Induction, and Effector Multifunction during Primary Infection Are Key Determinants for Early Immune Control.
IL-12-Dependent Cytomegalovirus-Specific CD4+ T Cell Proliferation, T-bet Induction, and Effector Multifunction during Primary Infection Are Key Determinants for Early Immune Control.
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DOI：
10.4049/jimmunol.1501589
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发表时间：
2016-01-15
期刊：
影响因子：
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通讯作者：
McDyer JF
中科院分区：
文献类型：
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作者：
Popescu I;Pipeling MR;Mannem H;Shah PD;Orens JB;Connors M;Migueles SA;McDyer JF
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CMV remains an important opportunistic pathogen in solid organ and hematopoietic cell 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 27 D+R− LTRs during primary CMV infection to determine whether acute CD4+ T cell parameters differentiated the capacity for viral control during early chronic infection. Unexpectedly, the T-box transcription factor, T-bet, was expressed at low levels in CD4+ compared to CD8+ T cells during acute primary infection. However, the capacity for in vitro CMV phosphoprotein 65 (pp65)-specific proliferation and CD4+T-bet+ induction differentiated LTR controllers from early viremic relapsers, correlating with granzyme B loading and effector multi-function. Further, impaired CMV-specific proliferative responses from relapsers, along with T-bet, and effector function could be significantly rescued, most effectively with pp65 antigen and combined exogenous IL-2 and IL-12. Acute CD4+ T cell CMV-specific proliferative and effector responses were highly IL-12-dependent in blocking studies. Additionally, we generated monocyte-derived dendritic cells (MDDC) using PBMC obtained during primary infection from relapsers and observed impaired MDDC differentiation, a reduced capacity for IL-12 production, but increased IL-10 production compared to controls, suggesting an Ag-presenting cell defect during acute CMV viremia. Together, these data show an important role for CMV-specific CD4+ effector responses in differentiating the capacity of high-risk LTRs to establish durable immune control during early chronic infection and provide evidence for IL-12 as a key factor driving these responses.