Medicine (St Vincent's) - Research Publications

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Author: Belz, Gabrielle ×

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    A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
    Koay, H-F ; Gherardin, NA ; Enders, A ; Loh, L ; Mackay, LK ; Almeida, CF ; Russ, BE ; Nold-Petry, CA ; Nold, MF ; Bedoui, S ; Chen, Z ; Corbett, AJ ; Eckle, SBG ; Meehan, B ; d'Udekem, Y ; Konstantinov, IE ; Lappas, M ; Liu, L ; Goodnow, CC ; Fairlie, DP ; Rossjohn, J ; Chong, MM ; Kedzierska, K ; Berzins, SP ; Belz, GT ; McCluskey, J ; Uldrich, AP ; Godfrey, DI ; Pellicci, DG (NATURE PUBLISHING GROUP, 2016-11)
    Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.
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    Unlike CD4+ T-cell help, CD28 costimulation is necessary for effective primary CD8+ T-cell influenza-specific immunity
    Seah, SGK ; Carrington, EM ; Ng, WC ; Belz, GT ; Brady, JL ; Sutherland, RM ; Hancock, MS ; La Gruta, NL ; Brown, LE ; Turner, SJ ; Zhan, Y ; Lew, AM (WILEY, 2012-07)
    The importance of costimulation on CD4(+) T cells has been well documented. However, primary CTLs against many infections including influenza can be generated in the absence of CD4(+) T-cell help. The role of costimulation under such "helpless" circumstances is not fully elucidated. Here, we investigated such a role for CD28 using CTLA4Ig transgenic (Tg) mice. To ensure valid comparison across the genotypes, we showed that all mice had similar naïve precursor frequencies and similar peak viral loads. In the absence of help, viral clearance was significantly reduced in CTLA4Ig Tg mice compared with WT mice. CD44(+) BrdU(+) influenza-specific CD8(+) T cells were diminished in CTLA4Ig Tg mice at days 5 and 8 postinfection. Adoptive transfer of ovalbumin-specific transgenic CD8(+) T cells (OT-I)-I cells into WT or CTLA4Ig Tg mice revealed that loss of CD28 costimulation resulted in impairment in OT-I cell division. As shown previously, neither viral clearance nor the generation of influenza-specific CD8(+) T cells was affected by the absence of CD4(+) T cells alone. In contrast, both were markedly impaired by CD28 blockade of "helpless" CD8(+) T cells. We suggest that direct CD28 costimulation of CD8(+) T cells is more critical in their priming during primary influenza infection than previously appreciated.