JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells

Clodagh Keohane, Shahram Kordasti, Thomas Seidl, Pilar Perez Abellan, Nicholas S. B. Thomas, Claire N. Harrison, Donal P. Mclornan, Ghulam J. Mufti

    Research output: Contribution to journalArticlepeer-review

    73 Citations (Scopus)

    Abstract

    CD4+ T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms (MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors (JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4+ T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4+ CD127low CD25high FOXP3+ T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)-17 cells increased. We also describe a functional ‘silencing’ of T helper cells both in vivo and in vitro and a blockade of pro-inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.
    Original languageEnglish
    Pages (from-to)60-73
    JournalBritish Journal of Haematology
    Volume171
    Issue number1
    Early online date15 Jun 2015
    DOIs
    Publication statusPublished - 1 Oct 2015

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