Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

Abstract

Key Points• Distinct T-cell patterns characterize the acute and chronic forms of cutaneous GVHD.• Increased TSLP expression is an indicator of acute cutaneous GVHD development.Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n 5 25), clGVHD (n 5 17), and csGVHD (n 5 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n 5 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4 1 T cells.Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-g-and IL-17-producing CD8

An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition

“…Indeed, Annunziato et al previously showed that the Th1/Th17 subset showed increased cytotoxic capacity and lower susceptibility to the Treg suppressive activity (52). Comparably, Brüggen et al observed a mixed Th1/Th17 signature in the skin of patients with lichenoid cGvHD (32).…”

“…In humans, there is a paucity of data. Dander et al showed an increase of Th17 cells in the blood of patients with active cGvHD (23), and a mixed Th1/Th17 signature was observed in the skin of patients with active disease (32). More recently, we identified candidate biomarkers (CCL14 and CD146) in the plasma of patients developing gastrointestinal (GI) GvHD that revealed an activated Th17-prone T cell population (CD4 + CD146 + CCR5 + T cells) participating in the pathogenesis of aGvHD (33).…”

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

“…In clinical cGVHD studies, increased IL-17 messenger RNA transcripts and significant Tc17 infiltration were demonstrated in skin, 72 whereas in the oral mucosa, Th17 infiltration dominated. Cytokines (IL-6, IL-21) known to support Th17 generation in GVHD are elevated in GVHD, [73][74][75][76] and STAT3, which drives Th17 development and Th17-dependent autoimmunity, 77 is essential for CD4 1 T-cell-mediated sclerodermatous cGVHD.…”

Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice

“…[27][28][29][30][31][32][33][34][35] Our previous report showed that B cells augmented Th17 expansion in the lung but not in the skin at 40 days after HCT. 15 Whether donor B cells and their antibodies affect Th17 expansion in the skin beyond 40 days after HCT has not been investigated.…”