title: A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency.
abstract: The competence of cellular immunity depends on a diverse T-cell receptor (TCR) repertoire arising from thymic output. Normal thymopoiesis arises from marrow-derived CD3(-)CD4(-)CD8(-) triple-negative T-cell progenitors (TN), which develop into mature single-positive (SP) CD4 or CD8 T cells after expressing both CD4 and CD8 (double-positive, DP) transiently, leading to de novo T-cell production. Interleukin-7 (IL7) is a singularly important common γ-chain IL involved in normal thymic development. Our previous work has demonstrated that γc cytokines fused with granulocyte-macrophage colony stimulating factor (GMCSF) at the N-terminus acquire unheralded biological properties. Therefore, to enhance thymopoiesis, we developed a novel biopharmaceutical based on the fusion of GMCSF and IL7, hereafter GIFT7. Systemic administration of GIFT7 leads to cortical thymic hyperplasia including the specific expansion of CD44(int)CD25(-) double-negative 1 (DN1) thymic progenitors. During murine cytomegalovirus (mCMV) infection of aged animals, GIFT7-mediated neo-thymopoiesis led to increased absolute numbers of viral-specific CD8(+) T cell. Our work demonstrated that thymic precursors can be therapeutically repopulated and its reconstitution leads to meaningful central and peripheral T-cell neogenesis, correcting immune dysfunction arising from age-associated thymic atrophy.
authors.affiliation: School of Medicine, Emory University , Atlanta, GA, USA ; Department of Hematology and Medical Oncology, The Winship Cancer Institute, Emory University , Atlanta, GA, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hsieh
authors.affiliation: School of Medicine, Emory University , Atlanta, GA, USA ; Department of Hematology and Medical Oncology, The Winship Cancer Institute, Emory University , Atlanta, GA, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Ng
authors.affiliation: Yerkes National Primate Research Center , Atlanta, GA, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Bosinger
authors.affiliation: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University , Montreal, QC, Canada.
authors.forename: Jian Hui
authors.initials: JH
authors.lastname: Wu
authors.affiliation: Yerkes National Primate Research Center , Atlanta, GA, USA.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Tharp
authors.affiliation: Department of Hematology and Medical Oncology, The Winship Cancer Institute, Emory University , Atlanta, GA, USA ; Yerkes National Primate Research Center , Atlanta, GA, USA.
authors.forename: Anapatricia
authors.initials: A
authors.lastname: Garcia
authors.affiliation: Department of Hematology and Medical Oncology, The Winship Cancer Institute, Emory University , Atlanta, GA, USA ; Department of Hematology and Medical Oncology, Emory University , Atlanta, GA, USA.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Hossain
authors.affiliation: Department of Hematology and Medical Oncology, The Winship Cancer Institute, Emory University , Atlanta, GA, USA.
authors.forename: Shala
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Hematology and Medical Oncology, The Winship Cancer Institute, Emory University , Atlanta, GA, USA ; Department of Hematology and Medical Oncology, Emory University , Atlanta, GA, USA.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.affiliation: Department of Hematology and Medical Oncology, The Winship Cancer Institute, Emory University , Atlanta, GA, USA ; Department of Hematology and Medical Oncology, Emory University , Atlanta, GA, USA ; Department of Pediatrics, Emory University , Atlanta, GA, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau