Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis

Abstract

IL-17 is a critical factor in the pathogenesis of psoriasis and other inflammatory diseases. The impact of γδ T cells, accounting for an important source of IL-17 in acute murine IL-23– and imiquimod-induced skin inflammation, in human psoriasis is still unclear. Using the polygenic CD18hypo PL/J psoriasis mouse model spontaneously developing chronic psoriasiform dermatitis due to reduced CD18/β2 integrin expression to 2–16% of wild-type levels, we investigated in this study the influence of adhesion molecule expression on generation of inflammatory γδ T cells and analyzed the occurrence of IL-17–producing γδ and CD4+ T cells at different disease stages. Severity of CD18hypo PL/J psoriasiform dermatitis correlated with a loss of skin-resident Vγ5+ T cells and concurrent skin infiltration with IL-17+, IL-22+, and TNF-α+ γδTCRlow cells preceded by increases in Vγ4+ T cells in local lymph nodes. In vitro, reduced CD18 levels promoted expansion of inflammatory memory-type γδ T cells in response to IL-7. Similar to IL-17 or IL-23/p19 depletion, injection of diseased CD18hypo PL/J mice with anti-γδTCR Abs significantly reduced skin inflammation and largely eliminated pathological γδ and CD4+ T cells. Moreover, CD18hypo γδ T cells induced allogeneic CD4+ T cell responses more potently than CD18wt counterparts and, upon adoptive transfer, triggered psoriasiform dermatitis in susceptible hosts. These results demonstrate a novel function of reduced CD18 levels in generation of pathological γδ T cells that was confirmed by detection of increases in CD18low γδ T cells in psoriasis patients and may also have implications for other inflammatory diseases.

Differential developmental requirement and peripheral regulation for dermal Vγ4 and Vγ6T17 cells in health and inflammation

“…Previous studies also identify scavenger receptor SCART2 is uniquely expressed in IL-17-producing γδT cells homing to the peripheral LN and dermis 15 . Furthermore, studies have shown that γδT cells can traffick between LN and skin 13, 16 , posing the question whether dermal γδT17 cells develop similarly as other peripheral γδT cells. Through bone marrow (BM) chimeras where BM cells were transplanted into lethally irradiated host mice, it showed that 90% of dermal γδT cells were from host origin whereas ~10% of dermal γδT cells were from donor BM 6 , suggesting BM cells may contain precursor cells that give rise to dermal γδT cells.…”

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

“…We speculate that local skin or oral inflammation may result in expansion of IL-17-producing cells in responding LNs, which could then home to the skin and act to generalize cutaneous inflammation. In this regard, γδT cells capable of producing IL-17 have been identified in the blood and skin of patients with psoriasis (3,15,16). Whereas expanded Vγ4 + Vδ4 + γδT17 cells may preferentially migrate to skin given CLA expression, it is possible that they may be recruited to other inflamed tissues where they could aggravate disease.…”

Leukocyte integrins: Role in leukocyte recruitment and as therapeutic targets in inflammatory disease

“…Mice bearing a hypomorphic CD18 mutation (CD18 hypo PL/J mice), resulting in decreased CD18 expression, develop psoriasiform dermatitis (Peters et al, 2006), featured by increased accumulation of CD4+ and γδ T cells (Gatzka et al, 2013) and decreased presence of regulatory T cells (Singh et al, 2013) at the skin lesions. β2-integrin deficiency has been previously associated with dysregulation of IL-17 production, due to defective neutrophil recruitment to peripheral tissues and subsequently reduced clearance of apoptotic neutrophils by macrophages (Stark et al, 2005; Moutsopoulos et al, 2014), as discussed in the following section.…”