A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency.

• Type of Material: Article
• Authors: Jeremy Hsieh, Emory University; Spencer Ng, Emory University; Steven Bosinger, Emory University; Jian Hui Wu, Yerkes National Primate Research Center; Gregory Tharp, Yerkes National Primate Research Center; Mohammad Hossain, Emory University; Shala Yuan, Emory University; Jacques Galipeau, Emory University; Edmund K Waller, Emory University
• Language: English
• Date: 2015-05
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Australasian Society for Immunology Inc.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/cti.2015.8
• Title of Journal or Parent Work: Clinical And Translational Immunology
• ISSN: 2050-0068
• Volume: 4
• Issue: 5
• Start Page: e37
• End Page: e37
• Grant/Funding Information: This work is supported by NIH grant (R01AI093881).
• Research Categories: Health Sciences, Immunology; Biology, General

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.