Two Distinct Mechanisms Underlying gamma delta T Cell-Mediated Regulation of Collagen Type I in Lung Fibroblasts

Idiopathic pulmonary fibrosis is a chronic intractable lung disease, leading to respiratory failure and death. Although anti-fibrotic agents delay disease progression, they are not considered curative treatments, and alternative modalities have attracted attention. We examined the effect of human gamma delta T cells on collagen type I in lung fibroblasts. Collagen type I was markedly reduced in a gamma delta T cell number-dependent manner following treatment with gamma delta T cells expanded with tetrakis-pivaloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2. Collagen type I levels remained unchanged on addition of gamma delta T cells to the culture system through a trans-well culture membrane, suggesting that cell-cell contact is essential for reducing its levels in lung fibroblasts. Re-stimulating gamma delta T cells with (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) reduced collagen type I levels without cell-cell contact, indicating the existence of HMBPP-induced soluble anti-fibrotic factors in gamma delta T cells. Adding anti-interferon-gamma (IFN-gamma)-neutralizing mAb restored collagen type I levels, demonstrating that human gamma delta T cell-derived IFN-gamma reduces collagen type I levels. Conversely, interleukin-18 augmented gamma delta T cell-induced suppression of collagen type I. Therefore, human gamma delta T cells reduce collagen levels in lung fibroblasts via two distinct mechanisms; adoptive gamma delta T cell transfer is potentially a new therapeutic candidate.