title: Immunomodulation of Selective Naive T Cell Functions by p110δ Inactivation Improves the Outcome of Mismatched Cell Transplantation.
abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) can treat certain hematologic malignancies due to the graft versus leukemia (GvL) effect but is complicated by graft versus host disease (GvHD). Expression of the p110δ catalytic subunit of the phosphoinositide 3-kinase pathway is restricted to leukocytes, where it regulates proliferation, migration, and cytokine production. Here, in a mouse model of fully mismatched hematopoietic cell transplantation (HCT), we show that genetic inactivation of p110δ in T cells leads to milder GvHD, whereas GvL is preserved. Inactivation of p110δ in human lymphocytes reduced T cell allorecognition. We demonstrate that both allostimulation and granzyme B expression were dependent on p110δ in naive T cells, which are the main mediators of GvHD, whereas memory T cells were unaffected. Strikingly, p110δ is not mandatory for either naive or memory T cells to mediate GvL. Therefore, immunomodulation of selective naive T cell functions by p110δ inactivation improves the outcome of allogeneic HSCT.
authors: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK. Electronic address: jmd83@medschl.cam.ac.uk.
authors: Jean-Marc
authors: JM
authors: Doisne
authors: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK.
authors: Christian M
authors: CM
authors: Hüber
authors: Laboratory for Lymphocyte Signaling and Development, Babraham Research Campus, The Babraham Institute, Cambridge CB22 3AT, UK.
authors: Klaus
authors: K
authors: Okkenhaug
authors: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK.
authors: Francesco
authors: F
authors: Colucci