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Gamma delta cells and immunosurveillance

Final Activity Report Summary - GAMMA_DELTA_IMMUNO (Gamma delta cells and immunosurveillance)

Molecular analysis of gamma/delta T cell responses provides insight into carcinoma trial data. Human peripheral blood gamma/delta T cells expand dramatically in response to the microbial metabolite HMB-PP which characterises many infections. Gamma/delta cells also recognise phosphorylated 'activators', and stress antigens on transformed cells. These observations underpin the hypothesis that gamma/delta cells can compose a powerful, non-MHC restricted component of immunotherapy for infections and tumours. However, the cells' optimal application requires an improved molecular understanding of their responses. Here, array comparisons with CD8 alpha/beta T cells have identified several molecular signatures of gamma/delta T cells. Among them, tumour - necrosis-factor-related-apoptosis-inducing-ligand (TRAIL) is strongly upregulated specifically by T cell receptor (TCR) gamma/delta and interleukin (IL)-2 stimulation. In stage-four carcinoma patients, a gamma/delta-TCR agonist (zoledronate) plus IL-2, but not zoledronate alone, sustained TRAIL levels and correlated positively with clinical outcome. These data clarify the biology and emphasise specific clinical potentials of gamma/delta T cells.

Distinct cytokine-driven responses of activated blood gamma/delta T cells: insights into unconventional T cell pleiotropy.
Human gamma/delta T cells comprise a small population of peripheral blood T cells that in many infectious diseases respond to the microbial metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), and rapidly expand to up to 50 % of CD3+ cells. Although this transitional response is widely viewed as pro-inflammatory and/or cytolytic, the increasing evidence that different cytokines drive distinct effector functions in alpha/beta T cells provoked us to use cDNA microarrays to explore in more detail the potential pleiotropy of HMB-PP-activated gamma/delta T cells. The related cytokines, IL-2, IL-4, or IL-21 each drove proliferation and comparable CD69 upregulation but induced distinct effector responses that were also different from the prototypic responses of alpha/beta T cells. Thus, the Th1-like response to IL-2 also included IL-5 and IL-13 that conversely were lacking from the IL-4 response. IL-21 induced a lymphoid homing phenotype and high expression of the follicular B-cell attracting chemokine CXCL13/BCA-1, thus defining a novel candidate TFH-like cell, which may play an important, hitherto underappreciated role in driving humoral immunity early in infection. Their broad and unanticipated plasticity may permit gamma/delta T cells to bridge innate and acquired immunity in a variety of contexts. These findings enhance our understanding of the multi-faceted human gamma/delta Tcell compartment, and have implications for the ongoing clinical application of cytokines and gamma/delta TCR agonists.