Norihiro Ueda 1 , 2 , 4 , Yasushi Uemura 3 , 4 , ∗ , Rong Zhang 3 , 4 , Shuichi Kitayama 1 , Shoichi Iriguchi 1 , Yohei Kawai 1 , Yutaka Yasui 1 , Minako Tatsumi 4 , Tatsuki Ueda 1 , Tian-Yi Liu 4 , 5 , Yasutaka Mizoro 6 , Chihiro Okada 6 , Akira Watanabe 6 , Mahito Nakanishi 7 , Satoru Senju 8 , Yasuharu Nishimura 8 , Kiyotaka Kuzushima 4 , 9 , Hitoshi Kiyoi 2 , Tomoki Naoe 10 , Shin Kaneko 1 , ∗∗
24 May 2018
CD4 + T helper (Th) cell activation is essential for inducing cytotoxic T lymphocyte (CTL) responses against malignancy. We reprogrammed a Th clone specific for chronic myelogenous leukemia (CML)-derived b3a2 peptide to pluripotency and re-differentiated the cells into original TCR-expressing T-lineage cells (iPS-T cells) with gene expression patterns resembling those of group 1 innate lymphoid cells. CD4 gene transduction into iPS-T cells enhanced b3a2 peptide-specific responses via b3a2 peptide-specific TCR. iPS-T cells upregulated CD40 ligand (CD40L) expression in response to interleukin-2 and interleukin-15. In the presence of Wilms tumor 1 (WT1) peptide, antigen-specific dendritic cells (DCs) conditioned by CD4-modified CD40L high iPS-T cells stimulated WT1-specific CTL priming, which eliminated WT1 peptide-expressing CML cells in vitro and in vivo. Thus, CD4 modification of CD40L high iPS-T cells generates innate lymphoid helper-like cells inducing bcr-abl-specific TCR signaling that mediates effectiveanti-leukemic CTL responses via DC maturation, showing potential for adjuvant immunotherapy against leukemia.
Kaneko and colleagues describe the generation of CD4 + T helper clone-derived iPSCs and differentiation of the cells into T-lineage cells, which had molecular signatures and functional properties more consistent with group 1 innate lymphoid cells. CD4 transduction and CD40 ligand high population purification of the regenerated cells enhanced the antigen-specific adjuvant responses via dendritic cells in an antigen-specific manner.