γδ cells making IL-17

In this issue of Blood, the functional attributes of human Vγ9Vδ2 T cells are firmly extended to the secretion of the proinflammatory cytokine IL-17.¹ 

Over the past 5 years, immunology has been marked by intense investigation of the production of IL-17 by various populations of T cells, and their contributions to immunity to infection, and autoimmunity. While initially the focus had been on T helper 17 (Th17) CD4⁺ T cells, more recent studies in various experimental models demonstrated a critical role for IL-17–producing γδ T cells.²  However, because these experiments had been done invariably with mice, a critical question remained unanswered: Do γδ T cells make any relevant contribution to IL-17 production in humans? In this issue of Blood, Caccamo et al show they do.¹ 

Various groups had hitherto consistently observed that the major subset of γδ T cells present in the human peripheral blood, characterized by the expression of a Vγ9Vδ2 T-cell receptor (TCR), contained very few (typically < 1%) IL-17 producers.^3,4  While this still holds for healthy individuals, Caccamo and colleagues identified a dramatically different scenario in the blood and cerebrospinal fluid of children suffering from bacterial meningitis: 60%–70% of their Vγ9Vδ2 T cells were IL-17⁺ (see figure). Interestingly, this pattern was reversed after successful antibacterial therapy.¹  Of note, Vγ9Vδ2 T cells are not the only human γδ T-cell subset capable of producing IL-17; Vδ1⁺ T cells were shown to make IL-17 specifically in the context of HIV-1 infection (in which they are markedly expanded).⁵ 

To further dissect the process of IL-17⁺ Vγ9Vδ2 T-cell differentiation, Caccamo and et al established an in vitro system, based on the combination of various cytokines, that generated 30%-40% IL-17⁺ Vγ9Vδ2 T cells with a phenotype matching that observed in vivo.¹  Again, these percentages were much greater than ever reported before (using different in vitro settings).⁴  The trick used by Caccamo and colleagues was to extend the in vitro cultures—that typically involved 6 days under Th17 polarizing conditions (using TGF-β, IL-1β, IL-6, IL-23)—with an extra week of expansion in IL-2–rich medium.¹  Under such conditions, IL-6 made an important contribution to the generation of IL-17⁺ γδ T cells, unlike what was previously reported for both human Vγ9Vδ2⁴  and murine γδ T cells.⁶  Thus, the work by Caccamo and colleagues provides both physiologic importance (in vivo) and methodologic advance (in vitro) to the study of IL-17⁺ Vγ9Vδ2 T cells.

Although both processes of differentiation and expansion of IL-17⁺ γδ T cells may involve common mediators, such as IL-1β and IL-23,^1,7  they must also display some key distinctive features. For example, while TGF-β is a potent antiproliferative cytokine for T cells, it is critically required for the differentiation of IL-17–producing T cells, particularly IL-17⁺ γδ T cells in both mice⁶  and humans.^1,4  It will therefore be important to understand the components of the inflammatory niches where human IL-17⁺ Vγ9Vδ2 T cells accumulate in vivo.

A key unanswered question regarding human γδ T cells is whether they follow similar rules of developmental preprogramming as their mouse counterparts.²  Thus, work from Ribot et al⁶  and Chien's group⁸  demonstrated that murine γδ T cells acquire their capacity to produce IL-17 or IFN-γ in the thymus, and defined TCRγδ and CD27 signals as key determinants of this thymic functional/developmental choice.²  Interestingly, human cord blood and neonatal peripheral blood γδ T cells have been shown to promptly secrete IFN-γ.⁹  In healthy adults, 50%-80% of blood Vγ9Vδ2 T cells produce IFN-γ,⁹  but < 1% make IL-17.⁴  In this scenario, the abundance of IL-17⁺ Vγ9Vδ2 T cells in meningitis patients described by Caccamo and colleagues is likely because of functional reprogramming (in the particular proinflammatory milieu driven by the infection) rather than to the expansion of a precommitted IL-17⁺ subset as suggested in murine models of infection.⁷  Thus, the degree of developmental preprogramming versus functional plasticity of γδ T cells²  requires further investigation in mice and humans.

Beyond the basic immunology issues to be resolved, future research should aim at finding clinical-grade tools to manipulate human IL-17⁺ γδ T cells and, more generally, all IL-17⁺ T cells. An attractive prospect is to interfere with de novo differentiation of IL-17⁺ T cells. Importantly, all known IL-17⁺ T-cell subsets, including IL-17⁺ Vγ9Vδ2 T cells¹  or IL-17⁺ Vδ1⁺ T cells,⁵  seem to depend on RORγt as a lineage-specifying transcription factor. Hence, the discovery and design of RORγt antagonists, as recently reported by Littman and colleagues,¹⁰  entail great promise for the therapeutic modulation of IL-17⁺ T cells in settings of chronic inflammation or autoimmunity.