Understanding the complexity of γδ T-cell subsets in mouse and human

Abstract

γδ T cells are increasingly recognized as having important functional roles in a range of disease scenarios such as infection, allergy, autoimmunity and cancer. With this has come realization that γδ cells are not a homogeneous population of cells with a single physiological role. Instead, ever increasing complexity in both phenotype and function is being ascribed to γδ cell subsets from various tissues and locations, and in both mouse and human. Here, we review this complexity by describing how diverse γδ cell subsets are generated in the murine thymus, and how these events relate to subsequent γδ subset function in the periphery. We then review the two major γδ cell populations in human, highlighting the several similarities of Vδ1(+) cells to certain murine γδ subsets, and describing the remarkable functional plasticity of human Vδ2(+) cells. A better understanding of this spectrum of γδ cell phenotypes should facilitate more targeted approaches to utilise their tremendous functional potential in the clinic.

Figure 1

Mouse γδ cell subsets in the thymus and periphery. (a) Thymic γδ subsets described by surface expression of; yellow triangles – CD27; green triangles – CD24; blue triangles CD44; purple triangles – CD25; and red triangles – CD122. Proposed developmental relationships between subsets are indicated by arrows, and potential for cytokine secretion is shown. (b) Peripheral γδ subsets described by tissue location, potential for cytokine secretion and surface markers, as described for (a). Gut γδ cells (i.e. γδ intraepithelial lymphocytes) express only low levels of CD122. IL-17A, interleukin-17A; IFN-γ, interferon-γ.

Figure 2

Human Vγ9Vδ2⁺γδ cells can be sub-divided using surface expression of CD45RA and CD27, and show remarkable functional plasticity after activation. (a) CD45RA⁺ CD27⁺ T_naive cells give rise to CD45RA⁻ CD27⁺ T_CM cells on activation with isopentenyl pyrophosphate + interleukin-2 (IPP+IL-2), but do not secrete interferon-γ (IFN-γ). Central memory T (T_CM) cells generate CD45RA⁻ CD27⁻ effector memory T (T_EM) cells after activation with IPP+IL-2, or CD45RA⁺ CD27⁻ T_EMRA cells in the presence of IL-15. T_EM cells can secrete abundant IFN-γ, whereas T_EMRA cells are mainly cytotoxic. Prol; proliferative capacity, Kill; cytotoxic capacity; red triangles indicate CD27 expression; blue triangles indicate CD45RA expression; green triangles indicate CD62L expression; (b) Vγ9Vδ2⁺ cells display extensive plasticity after activation with phosphoantigen [(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) or IPP] in the presence or absence of various cytokines as indicated. ‘?’ indicates uncertainty as to the potential of T_naive, T_CM, T_EM and T_EMRA to generate the indicated effector subsets. Expression of functionally relevant genes and characteristics are indicated. TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α.