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

Iulia Popescu, Matthew R. Pipeling, Hannah Mannem, Pali Dedhiya Shah, Jonathan B Orens, Mark Connors, Stephen A. Migueles, John F. McDyer

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)877-890
Number of pages14
JournalJournal of Immunology
Volume196
Issue number2
DOIs
StatePublished - Jan 15 2016

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Interleukin-12
Cytomegalovirus
Cell Proliferation
T-Lymphocytes
Lung
Infection
Phosphoproteins
Dendritic Cells
Granzymes
Viremia
Cell Transplantation
Interleukin-10
Interleukin-2
Monocytes
Cell Differentiation
Transplant Recipients
Tissue Donors
Mortality

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Popescu, Iulia; Pipeling, Matthew R.; Mannem, Hannah; Shah, Pali Dedhiya; Orens, Jonathan B; Connors, Mark; Migueles, Stephen A.; McDyer, John F.

In: Journal of Immunology, Vol. 196, No. 2, 15.01.2016, p. 877-890.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Mannem, Hannah

AU - Shah, Pali Dedhiya

AU - Orens, Jonathan B

AU - Connors, Mark

AU - Migueles, Stephen A.

AU - McDyer, John F.

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AB - 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.

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