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.
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The elusive role of γδ t cells
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
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
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)
Notes de l'éditeur
Through programmed rearrangements, fetal precursors generate successive waves of γδT cells expressing Vγ5Vδ1, Vγ1Vδ6.3 or Vγ6Vδ1 T cellreceptors (TCRs) with invariant or highly related junctional sequences. SKINT1 (selection and upkeep of intraepithelialT cells 1)-dependent interactions between invariant mouse Vγ5Vδ1+ T cells and thymic epithelial cells (TECs) induceearly commitment to a T helper 1 (TH1) cell-like phenotype and the acquisition of receptors that promote homing to theskin (CC-chemokine receptor 10 (CCR10)). Exit from the thymus depends on sphingosine 1-phosphate receptor 1(S1PR1). Vγ5Vδ1+ thymocytes then migrate to the epidermis where they acquire their typical dendritic morphology.SLAM-associated protein 1 (SAP1)-dependent interactions between Vγ1Vδ6.3+ T cells and thymic cells of haematopoieticorigin, presumably in conjunction with TCR engagement, upregulate expression of the transcription factor promyelocyticleukaemia zinc-finger (PLZF) and subsequent upregulation of CD4 and natural killer 1.1 (NK1.1) and production ofinterleukin-4 (IL-4), IL-13 and interferon-γ (IFNγ), which are under the control of the transcription factors PLZF and T-bet.Lack of TCR engagement by thymocytes expressing invariant Vγ6Vδ1 TCRs presumably leads to a transforming growthfactor-β (TGFβ)-dependent default pathway associated with acquisition of TH17 cell-like properties, under the control ofthe transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt), and the ability to home to uterine,vaginal, tongue and lung epithelia. AHR, aryl hydrocarbon receptor; EOMES, eomesodermin; R, receptor; SLAMF,signalling lymphocytic activation molecule F; TNF, tumour necrosis factor
*Immune cells are associated with and partly define tissues*Highly dendritic, highly intricate interlocking network mouse epidermis.*Human epidermis not exactly the same, but still informative.
Human intestine – gd cells in-between epithelial enterocytes. Serves function – early response to commonly found microbes at epithelial barriers (more innate type IR)TRAILR – TNF-related apoptosis-inducing ligand receptors
Structural analysis. Structural homology. gd TCR comprised of one gamma and one delta chian. Somatic recombination of gd t cells genes identified 2 x D elements – potential to create a wide range of TCRs.
Figure 1 | Sensing of cellular stress and infection by γδ T cells. γδ T cells canrecognize separately, additively or synergistically three sets of stress-induced stimuli:MHC-related and -unrelated T cell receptor (TCR) ligands (such as the weaklypolymorphic MHC class I-like human CD1c molecules and mouse T10 and T22 molecules,and microbial and endogenous phosphoantigens), various cell surface molecules (such asretinoic acid early transcript 1 (RAE1) and MHC class I polypeptide-related sequence A(MICA)) that engage the activating natural killer receptors (NKRs) such as NK group 2,member D (NKG2D), and/or danger-associated molecular patterns (DAMPs) orpathogen-associated molecular patterns (PAMPs) recognized by pattern recognitionreceptors (such as Toll-like receptors (TLRs) and dectin 1). IFNγ, interferon-γ; IL-17,interleukin-17; ULBP, cytomegalovirus UL16-binding protein.
This slides demonstrates that different gd T cells have different and sometimes contradictory effector functions.
Early response - *detects cellular stress and becomes activated *Programmed gd T cells release IL-17 to recruit and activate neutrophils, and CCL2 to recruit and activate monocyte or macrophages (Innate-like response)Late response - *anti-inflammatory cytokines (IL-10) *killing and suppression of ab T cells *promote tissue repair and cellular regeneration (as mentioned previously in context of mouse epidermis)
Vγ9Vδ2 have broad antitumour and antimicrobial properties.