Alloreactive effector T cells require the local formation of a proinflammatory environment to allow crosstalk and high avidity interaction with nonhematopoietic tissues to induce GVHD reactivity.
Based on clinical observations that donor T cells specific for minor histocompatibility antigens (MiHA) ubiquitously expressed on both hematopoietic and nonhematopoietic cells were detected in patients showing evident graft-versus-leukemia/lymphoma (GVL) reactivity with no or limited coinciding graft-versus-host disease (GVHD), we hypothesized that nonhematopoietic tissues may be relatively unsusceptible to the cytotoxic effect of MiHA-specific T cells under normal, noninflammatory conditions. To test this hypothesis, we investigated the reactivity of alloreactive T cells specific for ubiquitously expressed MiHA against skin-derived primary human fibroblasts. We demonstrated that this reactivity was not merely determined by their antigen-specificity, but was highly dependent on adhesion molecule expression. ICAM-1 expression on the fibroblasts upregulated under proinflammatory conditions and induced during cross-talk with the T cells was demonstrated to be a crucial factor facilitating formation of high avidity interactions with the T cells and subsequent efficient target cell destruction. Furthermore, we provide supporting evidence for the role of ICAM-1 in vivo by demonstrating that ICAM-1 expression on nonhematopoietic target cells was dependent on the presence of infiltrating activated T cells, as was illustrated by restricted ICAM-1 expression at the sites of T cell infiltration in skin biopsies of patients with acute GVHD (aGVHD), by the absence of ICAM-1 expression in the same biopsies in areas without T cell infiltration and by the absence of ICAM-1 expression in biopsies of patients without GVHD independent of the presence of infiltrating nonactivated T cells. In conclusion, under noninflammatory conditions, nonhematopoietic tissues are unsusceptible to the GVHD reactivity of alloreactive T cells due to their inability to establish high avidity interactions.
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. eb.van_der_zouwen@lumc.nl
Boris
B
van der Zouwen
Alwine B
AB
Kruisselbrink
Ekaterina S
ES
Jordanova
Caroline E
CE
Rutten
Peter A
PA
von dem Borne
J H Frederik
JH
Falkenburg
Inge
I
Jedema
D000208:Acute Disease; D001706:Biopsy; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D060833:Cellular Microenvironment / Q000276:immunology; D018920:Coculture Techniques; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D061251:Primary Cell Culture; D014162:Transfection; D014184:Transplantation, Homologous
D015778:Minor Histocompatibility Antigens; D018799:Intercellular Adhesion Molecule-1