School of Mathematics and Statistics - Research Publications

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Author: Evrard, Maximilien × Author: Speed, Terence × End date: 2023 × Start date: 2020 ×

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    Divergent molecular networks program functionally distinct CD8+ skin-resident memory T cells
    Park, SL ; Christo, SN ; Wells, AC ; Gandolfo, LC ; Zaid, A ; Alexandre, YO ; Burn, TN ; Schroeder, J ; Collins, N ; Han, S-J ; Guillaume, SM ; Evrard, M ; Castellucci, C ; Davies, B ; Osman, M ; Obers, A ; McDonald, KM ; Wang, H ; Mueller, SN ; Kannourakis, G ; Berzins, SP ; Mielke, LA ; Carbone, FR ; Kallies, A ; Speed, TP ; Belkaid, Y ; Mackay, LK (AMER ASSOC ADVANCEMENT SCIENCE, 2023-12-01)
    Skin-resident CD8+ T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.
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    Runx3 drives a CD8+ T cell tissue residency program that is absent in CD4+ T cells
    Fonseca, R ; Burn, TN ; Gandolfo, LC ; Devi, S ; Park, SL ; Obers, A ; Evrard, M ; Christo, SN ; Buquicchio, FA ; Lareau, CA ; McDonald, KM ; Sandford, SK ; Zamudio, NM ; Zanluqui, NG ; Zaid, A ; Speed, TP ; Satpathy, AT ; Mueller, SN ; Carbone, FR ; Mackay, LK (NATURE PORTFOLIO, 2022-08)
    Tissue-resident memory T cells (TRM cells) provide rapid and superior control of localized infections. While the transcription factor Runx3 is a critical regulator of CD8+ T cell tissue residency, its expression is repressed in CD4+ T cells. Here, we show that, as a direct consequence of this Runx3-deficiency, CD4+ TRM cells lacked the transforming growth factor (TGF)-β-responsive transcriptional network that underpins the tissue residency of epithelial CD8+ TRM cells. While CD4+ TRM cell formation required Runx1, this, along with the modest expression of Runx3 in CD4+ TRM cells, was insufficient to engage the TGF-β-driven residency program. Ectopic expression of Runx3 in CD4+ T cells incited this TGF-β-transcriptional network to promote prolonged survival, decreased tissue egress, a microanatomical redistribution towards epithelial layers and enhanced effector functionality. Thus, our results reveal distinct programming of tissue residency in CD8+ and CD4+ TRM cell subsets that is attributable to divergent Runx3 activity.