School of Mathematics and Statistics - Research Publications

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Author: Liao, Yang × Author: Smyth, Gordon × End date: 2022 × Start date: 2020 ×

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    Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria
    Studniberg, S ; Ioannidis, LJ ; Utami, RAS ; Trianty, L ; Liao, Y ; Abeysekera, W ; Li-Wai-Suen, CSN ; Pietrzak, HM ; Healer, J ; Puspitasari, AM ; Apriyanti, D ; Coutrier, F ; Poespoprodjo, JR ; Kenangalem, E ; Andries, B ; Prayoga, P ; Sariyanti, N ; Smyth, GK ; Cowman, AF ; Price, RN ; Noviyanti, R ; Shi, W ; Garnham, AL ; Hansen, DS (WILEY, 2022-04)
    Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.
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    Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis
    Sidwell, T ; Liao, Y ; Garnham, AL ; Vasanthakumar, A ; Gloury, R ; Blume, J ; Teh, PP ; Chisanga, D ; Thelemann, C ; Rivera, FDL ; Engwerda, CR ; Corcoran, L ; Kometani, K ; Kurosaki, T ; Smyth, GK ; Shi, W ; Kallies, A (NATURE PUBLISHING GROUP, 2020-01-14)
    Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.