Immunomodulation of selective naïve T cell functions by p110δ inactivation improves the outcome of allogeneic hematopoietic cell transplantation
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Doisne, J., Hüber, C. M., Okkenhaug, K., & Colucci, F. (2015). Immunomodulation of selective naïve T cell functions by p110δ inactivation improves the outcome of allogeneic hematopoietic cell transplantation. Cell Reports, 10 702-710. https://doi.org/10.1016/j.celrep.2015.01.002
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.
This work was supported by grants from Biotechnology and Biological Sciences Research Council, the Wellcome Trust (088621/Z/09/Z), and Leukaemia & Lymphoma Research (13010) to F.C.
Wellcome Trust (088621/B/09/Z)
External DOI: https://doi.org/10.1016/j.celrep.2015.01.002
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247257
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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