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 A, Mackay LK, Rahimpour A, Braun A, Veldhoen M, Carbone FR, Manton JH, Heath WR, Mueller SN
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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 LK, Braun A, Macleod BL, Collins N, Tebartz C, Bedoui S, Carbone FR, Gebhardt T
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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 LK, Wynne-Jones E, Freestone D, Pellicci DG, Mielke LA, Newman DM, Braun A, Masson F, Kallies A, Belz GT, Carbone FR
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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
Laura K. Mackay, Martina Minnich, Natasja A.M. Kragten, Yang Liao, Benjamin Nota, Cyril Seillet, Ali Zaid, Kevin Man, Simon Preston, David Freestone, Asolina Braun, Daniel G. Pellicci, Dale I. Godfrey, Gabrielle T. Belz, Marc Pellegrini, Thomas Gebhardt,
