Inflammation induces dermal Vγ4 ⁺ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

Abstract

Gamma delta (γδ) T cells represent a major IL-17 committed T-cell population (γδT17 cells) in the mouse dermis. Following exposure to the inflammatory agent imiquimod (IMQ) the Vγ4 + subset of γδT cells produce IL-17 in the skin and expand rapidly in draining lymph nodes (LNs). Local IMQ treatment in humans is known to exacerbate psoriasis skin lesion activity at distant sites. Whether expanded γδT17 cells sensitize distant sites to inflammation has been unknown. Here we show that expanded Vγ4 + γδT17 cells egress from LNs in a fingolimod (FTY720)-sensitive manner and use C-C chemokine receptor type 2 to accumulate in inflamed skin where they augment neutrophil recruitment and inflammation. They also travel to noninflamed skin and peripheral LNs and remain in elevated numbers at these distant sites for at least 3 mo. Sensitized mice show more rapid skin inflammation and greater proliferation and IL-17 production by Vγ4 + γδT cells upon imiquimod challenge. Transfer experiments confirm that memory-like Vγ4 + γδT17 cells respond more rapidly. Memory-like Vγ4 + γδT17 cells are distinguished by greater IL-1R1 expression and more proliferation in response to IL-1β. These findings establish that local skin inflammation leads to faster and stronger secondary responses to the same stimulus through longterm and systemic changes in the composition and properties of the dermal γδT-cell population.immunological memory | γδT cells | inflammation

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

“…It has recently been suggested that naive (uncommitted) gd T cells are continuously produced from embryonic day 16 and, upon recognition of the "model Ag" PE, might be able to initiate IL-17 production without prior commitment to the gdT17 lineage in the thymus (30,43 Ag-specific system (4) and in a recent study, CD3g and CD3d double haploinsufficient mice, which exhibit decreased signaling strength downstream of the TCR, lose a large fraction of their IFN-g-producing gd T cells during embryonic development, which is sustained during adulthood (44). TCR-Vg4 + gd T cells expand during imiquimod-induced skin inflammation and redistribute to previously noninflamed skin sites where they were more responsive to IL-1b than nonimiquimodsensitized gdT17 cells due to higher expression of IL-1R1 (45). The readily inducible expression of Il1r1 in TCR-Vg4 + gd T cells in a TCR-dependent or TLR1-or TLR2-dependent (46) manner, and thus the direct engagement of the Vg4 + gd-TCR by ligands in the inflamed skin, might explain their exquisite responsiveness to IL-1b plus IL-23 and subsequently result in the preponderance of TCR-Vg4 over TCR-Vg6 in induced gdT17 cells in vivo as compared with their in vitro-induced counterparts.…”

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

“…Depending on the context, the same effector functions that make γδ T cells an important arm of the immune system can alternatively contribute to the development, progression and exacerbation of various diseases. These harmful effects include roles in the pathogenesis of autoimmune conditions such as psoriasis, multiple sclerosis, and arthritis, as well as contributions to breast cancer metastasis and bone loss 3–7 . Given that the beneficial and deleterious effects of γδ T cells are largely attributable to the ability of these cells to rapidly produce high levels of inflammatory cytokines, it is important to understand the development and function of the major effector subtypes.…”

IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF–Producing γδ T Cells in the Muscle

“…These results suggest that Vg4 + Vd4 + CD27 2 cells preferentially accumulate in the muscle in EAM-induced mice. It has been reported that Vg4 + Vd4 + cells produce IL-17 and are involved in the development of collagen-induced arthritis (40) and psoriasis-like skin changes (41)(42)(43). By using intracellular cytokine staining, we found that the most of GM-CSF-producing gdT cells in the draining LNs and the muscle in EAM-induced mice were Vg4 + Vd4 + cells (Fig.…”