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

MV 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 CMVinfection 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 with CD8⁺ T cells during acute primary infection. However, the capacity for in vitro CMV phosphoprotein 65-specific proliferation and CD4⁺ T-bet⁺ induction differentiated LTR controllers from early viremic relapsers, correlating with granzyme B loading and effector multifunction. Furthermore, impaired CMV-specific proliferative responses from relapsers, along with T-bet, and effector function could be significantly rescued, most effectively with phosphoprotein 65 Ag 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. In addition, we generated monocyte-derived dendritic cells using PBMC obtained during primary infection from relapsers and observed impaired monocytederived dendritic cell differentiation, a reduced capacity for IL-12 production, but increased IL-10 production compared with controls, suggesting an APC defect during acute CMV viremia. Taken 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.