Characterisation and functional analysis of factors that define tissue-resident memory T cells and contribute to their sessile phenotype
Zusammenfassung der Projektergebnisse
A successful adaptive immune response needs to engage the B cell arm as well as the T cell arm of the immune system. One specialised subset of T cells providing long lasting protection and surveying epithelial surfaces upon resolution of infection are the long-lived, non-recirculating tissue-resident CD8+ memory T cells (TRM). These cells branch off from effector T cells and acquire a phenotype markedly different to circulating memory T cells. This project confirmed a common set of ~45 core signature genes shared by TRM from different organs and established the expression kinetics of those genes during TRM development. TGF-ß is a cytokine crucially required for the development of TRM and this project involved a detailed analysis of TGF-ß effects on CD8+ T cell differentiation. Microanalysis showed that the transcriptional changes induced by TGF-ß in vitro show a significant overlap with the transcription signature that distinguishes TRM from circulating T cells thereby corroborating TGF-ß as a major driver of this core signature. Particularly, this project investigated the role of IL-15 in the early development phase of TRM. The experiments showed a novel function of IL-15 apart from providing survival signals. Lack of IL-15 in vivo leads to elevated S1P1 and KLF2 levels on skin-immigrating CD8+ effector T cells together with the failure to upregulate CD69. These defects translate into lower numbers of effector CD8+ T cells in the skin of IL-15-/- mice during acute infection presumably due to their insufficient retention in the tissue. Addition of IL-15 to effector T cells in vitro confirmed that particularly complexed IL-15/IL-15Ra signals drive transcriptional changes in S1P1, KLF2 and CD69 via the JAK - STAT - PI3K - Akt pathway. The IL-15 source in skin was addressed using IL-15emGFP mice and was found to be derived from keratinocytes and Langerhans cells. Furthermore, the importance of IL-15 in other tissues than skin was tested in the LCMV model. TRM were found to be dependent on IL-15 in salivary glands and kidney, but IL-15 was dispensable in gut, female reproductive tract, lymph nodes, spleen or thymus. A subsequent study of human CD8+ T cells confirmed the results found in the mouse model. In vitro work on isolated CD8+ T cells extended the findings on the down-modulation of S1P1 and KLF2 by IL-15 signalling with TGF-ß found to be playing a supportive role. Furthermore, human CD8+ T cells that showed CD69 and CD103 upregulation in vivo, expressed the lowest levels of S1P1 and KLF2 compared to CD69+ cells or double-negative CD8+ in line with the notion that TRM are CD69+ CD103+ cells that downregulate S1P1 to remain tissue-resident. Overall this project provided support for the delineation of a distinct TRM–lineage with its own gene signature that distinguishes them from re-circulating cells, the project validated TGF-ß as a major driver of this core signature and uncovered IL-15 as a factor promoting not only survival but also TRM residency.
Projektbezogene Publikationen (Auswahl)
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Analysis of factors regulating development and persistence of tissue-resident memory T cells. DGfI Annual Meeting 2014, Bonn
Asolina Braun
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Persistence of skin-resident memory T cells within an epidermal niche. Proc Natl Acad Sci USA. 2014 Apr 8;111(14):5307-12
Zaid, Ali; Mackay, Laura K.; Rahimpour, Azad; Braun, Asolina; Veldhoen, Marc; Carbone, Francis R.; Manton, Jonathan H.; Heath, William R. & Mueller, Scott N.
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Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention. J Immunol. 2015 Mar 1;194(5):2059-63
Mackay, Laura K.; Braun, Asolina; Macleod, Bethany L.; Collins, Nicholas; Tebartz, Christina; Bedoui, Sammy; Carbone, Francis R. & Gebhardt, Thomas
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T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate. Immunity. 2015 Dec 15;43(6):1101-11
Mackay, Laura K.; Wynne-Jones, Erica; Freestone, David; Pellicci, Daniel G.; Mielke, Lisa A.; Newman, Dane M.; Braun, Asolina; Masson, Frederick; Kallies, Axel; Belz, Gabrielle T. & Carbone, Francis R.
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Hobit and Blimp1 instruct a universal transcriptional program of tissueresidency in lymphocytes. Science 22 Apr 2016:
Vol. 352, Issue 6284, pp. 459-463
Mackay, Laura K.; Minnich, Martina; Kragten, Natasja A. M.; Liao, Yang; Nota, Benjamin; Seillet, Cyril; Zaid, Ali; Man, Kevin; Preston, Simon; Freestone, David; Braun, Asolina; Wynne-Jones, Erica; Behr, Felix M.; Stark, Regina; Pellicci, Daniel G.; Godfrey, Dale I.; Belz, Gabrielle T.; Pellegrini, Marc; Gebhardt, Thomas; ... & van Gisbergen, Klaas P. J. M.
