The role of interleukin-21 in gamma delta T lymphocyte memory development
Final Report Abstract
Human Vγ9/Vδ2 T cells comprise a small population of peripheral blood T cells that expand in many infectious diseases and respond specifically towards the microbial low molecular weight metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP). However, the response of Vγ9/Vδ2 T cells also depends on the presence of co-stimulatory cytokines. We recently identified IL-21 as a potent co-stimulator of human HMB-PP reactive Vγ9/Vδ2 T cells. IL-21 is a novel cytokine that is related to IL-2 and IL-4, and produced by activated CD4 T cells but not by B cells or monocytes. In presence of either IL-2, IL-4, or IL-21, HMBPP activated Vγ9/Vδ2 T cells proliferate and express CD69 and ICAM-1. Yet, only IL-2 stimulated cells display a pro-inflammatory Th1-like phenotype, express IFN-γ, TNF-α, TRAIL, and MIP-1α, and lack the homing receptor CD62L, while IL-4 stimulated cells display a Th2-like phenotype characterised by expression of IL-4 and GATA3. IL-21 in contrast appears to favour the polarisation of Vγ9/Vδ2 T cells into a CD62L+ central memorylike phenotype. Gene expression profiling on Hver2.1.1 microarrays containing about 15,000 genes revealed that IL-21 stimulated Vγ9/Vδ2 T cells unexpectedly express the follicular chemokine BCA-1/BCL/CXCL13. CXCL13 expression in these cells was confirmed by RTPCR and ELISA analysis. As Vγ9/Vδ2 T cells cluster in germinal centres, and follicular CD4 T cells were recently shown to be a major source of IL-21, these data imply that HMB-PP reactive CD62L+ Vγ9/Vδ2 T cells may play an important role in the development of humoral immunity during the early phase of antimicrobial responses. Overall, the microarray data imply a broad flexibility of Vγ9/Vδ2 T cells that, dependent on the local microenvironment, can assume Th1- and Th2-like effector functions, and provide B cell help in secondary lymphoid tissues.
Publications
- Caccamo N, Dieli F, Wesch D, Jomaa H, Eberl M. Sex-specific phenotypical and functional differences in peripheral human Vγ9/Vδ2 T cells. J Leukoc Biol. 2006 Apr;79(4):663-6.
- Ali Z, Shao L, Halliday L, Reichenberg A, Hintz M, Jomaa H, Chen ZW. Prolonged (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate-driven antimicrobial and cytotoxic responses of pulmonary and systemic Vγ2Vδ2 T cells in macaques. J Immunol. 2007 Dec 15;179(12):8287-96.
- Vermijlen D, Ellis P, Langford C, Klein A, Engel R, Willimann K, Jomaa H, Hayday AC, Eberl M. Distinct cytokine-driven responses of activated blood γδ T cells: insights into unconventional T cell pleiotropy. J Immunol. 2007 Apr 1;178(7):4304-14.
