Overview of γδ-T Cells

Alex WangNov. 19, 2015

Functions of γδ T cells• In mice, γδ T cells play a role in pathogen clearance, tissue repair, tumor

surveillance, immunoregulation, autoimmunity, allergy, and carcinogenesis

• γδ T cells downregulate inflammation and mediate wound repair in the skin, but also have been shown to exacerbate disease (psoriasis)

• γδ T cells has been linked to autoimmune disorders and can also interfere with cancer immunosurveillance

• Conversely, immune regulation by lung resident γδ T-cells is crucial for down regulating inflammation and inducing tissue repair in different models of infection or stress induced emphysema

• γδ T-cells are involved in mounting an effective immune response against pathogens including Staphylococcal aureus, Listeria monocytogenes, Escherichia coli, Bacillus subtilis, and Mycobacterium tuberculosis

• Thus, γδ T-cells can serve as important players in both immunity and tissue homeostasis, but also contribute to immune dysfunction and inflammatory pathogenesis.

Six of the best γδ T cell functions

αβ vs γδ T cells

• Both subsets develop in thymus and undergo V(D)J recombination, defined by either γδ or αβ TCR complex

• αβ secondary lymphoid organs; γδ epithelial surfaces

• αβ recognize peptide ligands in context of MHC class I/II; γδ does not recognize ligand in MHC-restricted manner - respond to broad range of antigens, including lipids

• αβ cells naïve upon exit from thymus, acquire effector role in periphery; γδ cells acquire effector function in thymus and exhibit limited plasticity upon arrival in periphery

γδ T cell commitment • Both γδ and αβ T cells arise from common CD4-

CD8- (DN) precursor in thymus• Final split of γδ and αβ cells occur at DN3 stage of

T-cell development (CD44-CD25+) • Most immature γδ T cells in thymus are CD24hi, but

can switch to αβ lineage • Cannot fate switch upon downregulation of CD24hi

• CD73 marks γδ T cell commitment – CD24hiCD73+ cannot switch to αβ lineage

• 90% of peripheral γδ T cells are CD73+

γδ T cell effector fates

• Many γδ T cells acquire their effector fate during development in the thymus and exhibit limited plasticity upon arrival in the periphery

• 3 subsets: – IL-17 producers CD27- (lymph node, dermis), Vγ2+

– IFN-γ producers CD27+ (spleen, epidermis), Vγ1+

– innate-like CD27+, NK1.1+ • Simultaneous production of IFN-γ and IL-4• Can rapidly produce IL-17 or IFN-γ in response to cytokine

stimulation w/o TCR engagement • Express Vγ1.1, Vδ6.3/6.4

Current models for acquisition of γδ T cell effector fates

Origins of γδ T cell Effector Subsets: A Riddle Wrapped in Enigma. Fahl et al. Journal of Immunology, Nov. 2014.

Model for TCR signal strength in determining αβ versus γδ lineage commitment, and effector function differentiation. Note γδ T cells are CD4-CD8-.

Gamma delta T-cell differentiation and effector function programming, TCR signal strength, when and how much? Zarin et al. Cellular Immunology, 2015.

Functional differentiation of murine γδ T cells. Molecular pathways associated with thymic pre-programming and peripheral activation of discrete cytokine-producing subsets of murine γδ T cells.

Epigenetic and transcriptional regulation of γδ T cell differentiation: Programming cells for responses in time and space. Schmolka et al. Seminars in immunology, 2015.

γδ T cell by locationDermal γδ T cells: What have we learned? O’Brien. Cellular immunology, Jul. 2015.

γδ T cell: IL17 Production in Dermis

• Dermal, motile γδ T cells are the major source of skin IL-17 during the early stages of infection

• Staining: TCRγδ, TCRβ, IL-17A, CCR6, IL-7Rα, CD103, Vγ5, CD45.2, CD45.1 [CD3+?]

• Sorting: TCRγδ+, CCR6+, TCRβ-, IL-7Rα+ (for dermal). CCR6- is epidermal.

• Source: Cutting Edge: Identification of a Motile IL-17–Producing γδ T Cell Population in the Dermis. Gray et al. Journal of Immunology, Jun 2011.

γδ T cell: IL17 Production in Dermis

• Dermal γδ T cells are the major source of IL-17 in the skin upon IL-23 stimulation

• γδ T cells are required for dermal inflammation and hyperplasia

• Dermal γδ T cells from human psoriatic skin are increased and produce IL-17

• CD3 intensity higher in epidermal skin cell

References• Origins of γδ T cell Effector Subsets: A Riddle Wrapped in Enigma. Fahl

et al. Journal of Immunology, Nov. 2014. • Gamma delta T-cell differentiation and effector function programming,

TCR signal strength, when and how much? Zarin et al. Cellular Immunology, 2015.

• Epigenetic and transcriptional regulation of γδ T cell differentiation: Programming cells for responses in time and space. Schmolka et al. Seminars in immunology, 2015.

• Dermal γδ T cells: What have we learned? O’Brien. Cellular immunology, Jul. 2015.

• Cutting Edge: Identification of a Motile IL-17–Producing γδ T Cell Population in the Dermis. Gray et al. Journal of Immunology, Jun 2011.