Christina L. Roark

Exacerbation of Collagen-Induced Arthritis by Oligoclonal, IL-17-Producing γδ T Cells

Murine γδ T cell subsets, defined by their Vγ chain usage, have been shown in various disease models to have distinct functional roles. In this study, we examined the responses of the two main peripheral γδ T cell subsets, Vγ1+ and Vγ4+ cells, during collagen-induced arthritis (CIA), a mouse model that shares many hallmarks with human rheumatoid arthritis. We found that whereas both subsets increased in number, only the Vγ4+ cells became activated. Surprisingly, these Vγ4+ cells appeared to be Ag selected, based on preferential Vγ4/Vδ4 pairing and very limited TCR junctions. Furthermore, in both the draining lymph node and the joints, the vast majority of the Vγ4/Vδ4+ cells produced IL-17, a cytokine that appears to be key in the development of CIA. In fact, the number of IL-17-producing Vγ4+ γδ T cells in the draining lymph nodes was found to be equivalent to the number of CD4+αβ+ Th-17 cells. When mice were depleted of Vγ4+ cells, clinical disease scores were significantly reduced and the incidence of disease was lowered. A decrease in total IgG and IgG2a anti-collagen Abs was also seen. These results suggest that Vγ4/Vδ4+ γδ T cells exacerbate CIA through their production of IL-17.

γδ T-cell receptors : functional correlations

Summary:u2002 The γδ T‐cell receptors (TCRs) are limited in their diversity, suggesting that their natural ligands may be few in number. Ligands for γδTCRs that have thus far been determined are predominantly of host rather than foreign origin. Correlations have been noted between the Vγ and/or Vδ genes a γδ T cell expresses and its functional role. The reason for these correlations is not yet known, but several different mechanisms are conceivable. One possibility is that interactions between particular TCR‐V domains and ligands determine function or functional development. However, a recent study showed that at least for one ligand, receptor specificity is determined by the complementarity‐determining region 3 (CDR3) component of the TCR‐δ chain, regardless of the Vγ and/or Vδ. To determine what is required in the TCR for other specificities and to test whether recognition of certain ligands is connected to cell function, more γδTCR ligands must be defined. The use of recombinant soluble versions of γδTCRs appears to be a promising approach to finding new ligands, and recent results using this method are reviewed.

IL-17-Producing γδ T Cells

IL‐17 is produced not only by CD4+ αβ T cells, but also CD8+ αβ T cells, NKT cells, and γδ T cells, plus some non‐T cells, including macrophages and neutrophils. The ability of IL‐17 to deploy neutrophils to sites of inflammation imparts this cytokine with a key role in diseases of several types. Surprisingly, γδ T cells are responsible for much of the IL‐17 produced in several disease models, particularly early on.

IL-17-producing gammadelta T cells.

IL‐17 is produced not only by CD4+ αβ T cells, but also CD8+ αβ T cells, NKT cells, and γδ T cells, plus some non‐T cells, including macrophages and neutrophils. The ability of IL‐17 to deploy neutrophils to sites of inflammation imparts this cytokine with a key role in diseases of several types. Surprisingly, γδ T cells are responsible for much of the IL‐17 produced in several disease models, particularly early on.

Airway hyperresponsiveness through synergy of γδ T cells and NKT cells

Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred γδ T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vγ1+Vδ5+ γδ T cells enhanced AHR. Surprisingly, OVA-specific αβ T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses.

Allergic Airway Hyperresponsiveness-Enhancing γδ T Cells Develop in Normal Untreated Mice and Fail to Produce IL-4/13, Unlike Th2 and NKT Cells

Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like invariant NKT (iNKT) cells, develops under the influence of enhancing and inhibitory γδ T cells. The AHR-enhancing cells belong to the Vγ1+ γδ T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR. However, unlike Th2 cells, the AHR enhancers arise in untreated mice, and we show here that they exhibit their functional bias already as thymocytes, at an HSAhigh maturational stage. In further contrast to Th2 cells and also unlike iNKT cells, they could not be stimulated to produce IL-4 and IL-13, consistent with their synergistic dependence on iNKT cells in mediating AHR. Mice deficient in IFN-γ, TNFRp75, or IL-4 did not produce these AHR-enhancing γδ T cells, but in the absence of IFN-γ, spontaneous development of these cells was restored by adoptive transfer of IFN-γ-competent dendritic cells from untreated donors. The i.p. injection of OVA/aluminum hydroxide restored development of the AHR enhancers in all of the mutant strains, indicating that the enhancers still can be induced when they fail to develop spontaneously, and that they themselves need not express TNFRp75, IFN-γ, or IL-4 to exert their function. We conclude that both the development and the cytokine potential of the AHR-enhancing γδ T cells differs critically from that of Th2 cells and NKT cells, despite similar influences of these cell populations on AHR.

Macrophages Express Multiple Ligands for γδ TCRs

As only a handful of ligands have been identified, the general nature of the ligands recognized by gammadelta T cells remains unresolved. In this study, soluble multimerized gammadelta T cell receptors (smTCRs) representing the TCRs of two gammadelta T cell subsets common in the mouse were used to detect and track their own ligands. Ligands for both subsets were found on resident peritoneal macrophages taken from untreated mice, and the expression of both was further induced by Listeria monocytogenes infection. Nevertheless, the two types of ligand differ from one another in abundance, in the kinetics of their induction following Listeria infection, and in their ability to be induced by in vitro culture with lipopolysaccharide (LPS). Surprisingly, because both are detectable on normal macrophages, these host-derived ligands are likely expressed constitutively, but are induced to higher levels of expression by stress or inflammation. In contrast to T22 and other known cell surface ligands for gammadelta T cells in mice and humans, expression of these smTCR-defined ligands does not depend on beta2-microglobulin, suggesting that they are not MHC class I or class I-like molecules.