Open AccessA GMCSF and IL7 fusion cytokine leads to functional thymic‐dependent T‐cell regeneration in age‐associated immune deficiency
Author(s) -
Hsieh Jeremy,
Ng Spencer,
Bosinger Steve,
Wu Jian Hui,
Tharp Gregory K,
Garcia Anapatricia,
Hossain Mohammad S,
Yuan Shala,
Waller Edmund K,
Galipeau Jacques
Publication year - 2015
Publication title -
clinical and translational immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.321
H-Index - 34
ISSN - 2050-0068
DOI - 10.1038/cti.2015.8
Subject(s) - biology , lymphopoiesis , cd8 , immunology , t cell , thymic involution , immune system , il 2 receptor , cytokine , progenitor cell , microbiology and biotechnology , stem cell
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 γ c 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.