The roles of the white blood cell subset γδ t cells within the human body are yet to be fully described. Current literature has detailed several critical functions that vary dramatically between different γδ t cells. Understanding how these elusive cells influence our immune systems will provide an opportunity to utilise their functions to assist medical treatments for a range of pathologies including cancer, diabetes, and bacterial infections. Please send correspondence to Philip Voyias at P.D.Voyias@Warwick.ac.uk.

1. Thursday 10th March 2011
Philip Voyias
Biomedical Science, the University of Warwick
P.D.Voyias@Warwick.ac.uk

2.  Functions of γδ T cells differ according to:
• Tissue distribution of the cells (the local microenvironment or niche)
• Structure of their antigen receptors
• How and what stage of the immune response they have become activated
 γδ T cells are non-conventional, innate-like or transitional T cells
 They have immunoregulation and immunosurveillance roles
 Functional programming
 Tissue restriction
 Mechanisms of cellular sensing
 Contribution to inflammatory immune response

3. Functional programming of γδ T cell subsets
Developmental programming of mouse γδ T cell subsets accounts for their:
• Restricted tissue location
• Homogeneous TCR repertoire
• Distinct functional properties
Thymus
Figure- Bonneville, M. (2010) Nat Rev Immunol

4. • In the skin intraepidermal mouse Vγ5Vδ1 DETCs can recognise stressed keratinocytes
• Contribute to epithelial cell homeostasis (production of factors including KGFs, IGF1)
• DETCs become activated in skin wounds through TCR stimulation
• Recruit macrophages that promote wound repair
Figures- Hayday, A. (2009) Henry Stewart Talks

5.  Cytotoxic activity: can kill infected, activated or transformed cells
 eg mouse Vγ7Vδ4 T cells in intestinal mucosa can induce apoptosis via:
• engagement of death-inducing receptors (FAS and TRAILR)
• release of cytotoxic effector molecules (perforin and granzymes)
 Early response to commonly found microbes (e.g gram positive
Listeria monoctogenes)
Figure- Hayday, A. (2009) Henry Stewart Talks

6. Figure- Hayday, A. (2009) Henry Stewart Talks

7. HOWEVER:
• γδ T cells express essentially invariant receptors (No nucleotides at
junctions, no TdT)
• Interactions between γδ TCRs and stress induced ligands involve
recurrent germline motifs
Table- Carding, S. R. (2002) Nat Rev Immunol

8. • γδ T cells can recognise separately, additively or synergistically three
sets of stress - induced stimuli
• Allows rapid induction of effector functions following detection of
tissue stress
Figure adapted from- Bonneville, M. (2010) Nat Rev Immunol

9. Pre-activated γδ T cell subsets undertake a number
of effector functions upon stress detection
Table adapted from- Bonneville, M. (2010) Nat Rev Immunol

10. Figure- Carding, S. R. (2002) Nat Rev Immunol

11.  γδ T cell subsets undergo functional programming in thymus
 Show extensive functional plasticity
 Sense cellular stress
 Contribute to different stages of inflammatory immune responses
 γδ T cells thus are for assisting and modulating both adaptive and
innate immune responses and promoting epithelial cell homeostasis
 Innate features γδ T cells provide the potential for new
immunotherapeutic approaches:
• Human Vγ9Vδ2 T cell agonists (eg synthetic phosphoantigens –
bromohydrin pyrophosphate) in phase I and II clinical trials
Stabilized disease in patients with cancers and chronic viral infections

12. • Bonneville, M., R. L. O’Brien, and W. K. Born. (2010) γδ T cell effector functions: a blend of innate
programming and acquired plasticity. Nat Rev Immunol 10:467-478
• Carding, S. R., and P. J. Egan. (2002) γδ T cells: Functional plasticity and heterogeneity. Nat Rev
Immunol 2: 336-345
• Barbee, S. D. et al. (2011) Skint-1 is a highly specific, unique selecting component for epidermal T cells.
Proc Natl Acad Sci USA 108:3330-3335
• Wong, G. W. and Zuniga-Pflucker, J. C. (2010) Gamma delta and alpha beta T cell lineage choice:
resolution by a stronger sense of being. Semin Immunol 22:228-236
• Archbold, J. K. (2009) To be γδ or not to be γδ? Signalling pathways in αβ versus γδ T cell maturation.
Sci Signal 2:100-108
• Martin. B., et al (2009) Interleukin-17-producing γδ T cells selectively expand in response to pathogen
products and environmental signals. Immunity 31:181-183
• Hayday, A. C. (2009) γδ T cells and the lymphoid stress-surveillance response. Immunity 31:184-196
• Wilhelm, M. et al. (2003) γδ T cells for immune therapy of patients with lymphoid malignancies. Blood
102:7450-7457
• Hayday, A. (2009) "Innate-like lymphocytes - Part I", in Gordon, S. (ed.), Innate Immunity: Host
recognition and response in health and disease, The Biomedical & Life Sciences Collection, Henry
Stewart Talks Ltd, London (online at http://0-hstalks.com.pugwash.lib.warwick.ac.uk/bio)