γδ cells involved in contact sensitivity preferentially rearrange the Vγ3 region and require interleukin‐7

112

Substances that penetrate the skin surface can act as allergens and induce a T cell-mediated inflammatory skin disease called contact hypersensitivity (CHS). IL-17 is a key cytokine in CHS and was originally thought to be produced solely by CD4+ T cells. However, it is now known that several cell types including γδ T cells can produce IL-17. Here, we determine the role of γδ T cells, especially the dendritic epidermal T cells (DETC), in CHS. By use of a well-established model for CHS where dinitroflourobenzen (DNFB) is used as allergen, we found that γδ T cells are important players in CHS. Thus, an increased number of IL-17 producing DETC appear in the skin following exposure to DNFB in WT mice, and DNFB-induced ear-swelling is reduced by approximately 50% in TCRδ−/− mice compared to WT mice. In accordance, DNFB-induced ear-swelling was reduced by approximately 50% in IL-17−/− mice. We show that DNFB triggers DETC activation and IL-1β production in the skin, and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETC activated in vitro by incubation with anti-CD3 and IL-1β produce IL-17. Importantly, we demonstrate that the IL-1 receptor antagonist anakinra significantly reduces CHS responses as measured by decreased ear-swelling, inhibition of local DETC activation and a reduction in the number of IL-17+ γδ T cells and DETC in the draining lymph nodes. Taken together, we show that DETC become activated and produce IL-17 in an IL-1β-dependent manner during CHS suggesting a key role for DETC in CHS.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL-1β–Dependent Activation of Dendritic Epidermal T Cells in Contact Hypersensitivity

Nielsen

Lovato

MacLeod

et al. 2014

112

“…␥␦ T cells abrogate oral tolerance measured by Ig production (44). Other reports have shown that ␥␦ T cells were indispensable in successful transfer of contact hypersensitivity by T cells (45,46). In contrast, ␥␦ T cells may also participate actively in the suppression of the ␣␤ T cell response (47,48).…”

Section: Discussionmentioning

confidence: 97%

Characterization of Lung γδ T Cells Following Intranasal Infection withMycobacterium bovisBacillus Calmette-Guérin

Dieli

Iványi

Marsh

et al. 2003

Self Cite

The lungs are considered to have an impaired capacity to contain infection by pathogenic mycobacteria, even in the presence of effective systemic immunity. In an attempt to understand the underlying cellular mechanisms, we characterized the γδ T cell population following intranasal infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG). The peak of γδ T cell expansion at 7 days postinfection preceded the 30 day peak of αβ T cell expansion and bacterial count. The expanded population of γδ T cells in the lungs of BCG-infected mice represents an expansion of the resident Vγ2 T cell subset as well as an influx of Vγ1 and of four different Vδ gene-bearing T cell subsets. The γδ T cells in the lungs of BCG-infected mice secreted IFN-γ following in vitro stimulation with ionomycin and PMA and were cytotoxic against BCG-infected peritoneal macrophages as well as against the uninfected J774 macrophage cell line. The cytotoxicity was selectively blocked by anti-γδ TCR mAb and strontium ions, suggesting a granule-exocytosis killing pathway. Depletion of γδ T cells by injection of specific mAb had no effect on the subsequent developing CD4 T cell response in the lungs of BCG-infected mice, but significantly reduced cytotoxic activity and IFN-γ production by lung CD8 T cells. Thus, γδ T cells in the lungs might help to control mycobacterial infection in the period between innate and classical adaptive immunity and may also play an important regulatory role in the subsequent onset of αβ T lymphocytes.

“…In contrast, IL-7 is a keratinocyte-derived growth factor important for the development of ␥␦T cells, including mouse dendritic epidermal T cells (DETC) (27). Expression of this cytokine is increased in psoriasis (28), and injection of an anti-IL-7 Ab inhibits ␥␦T cell accumulation in lymph nodes following skin sensitization (29,30). Moreover, transgenic mice overexpressing IL-7 in keratinocytes develop a lymphoproliferative skin disease (31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Studies Using Leukemia Inhibitory Factor (LIF) Knockout Mice and a LIF Adenoviral Vector Demonstrate a Key Anti-Inflammatory Role for This Cytokine in Cutaneous Inflammation

Zhu

Oishi

Lee

et al. 2001

Previous work has implicated the cytokine leukemia inhibitory factor (LIF) in cutaneous inflammation, although results have differed as to whether LIF is pro- or anti-inflammatory in this setting. We examined edema, inflammatory cell infiltration, and cytokine responses following CFA injection in the adult mouse footpad. Inflammatory cell infiltration and edema are significantly enhanced when CFA is injected in LIF knockout mice as compared with injection of wild-type littermates. Moreover, local injection of an adenoviral vector encoding LIF suppresses both measures of inflammation. In contrast, injection of an adenoviral vector encoding β-galactosidase has no discernable effect on inflammation. In addition, comparison of the CFA responses in LIF knockout vs wild-type skin reveals that LIF is an important regulator of IL-1β, IL-6, IL-7, IL-2Rα, and IFN-γ in cutaneous inflammation. These and our previous data indicate that both endogenous and exogenous LIF are anti-inflammatory in the CFA model and that LIF is a key regulator of the cytokine cascade. The results also indicate that adenoviral gene delivery can be an effective therapeutic approach in this paradigm.