Tubulitis in renal allograft rejection: role of transforming growth factor-[beta] and interleukin-15 in development and maintenance of CD103+ intraepithelial T cells1.
Wong, Wai Keong; Robertson, Helen; Carroll, Helen P.; Ali, Simi; Kirby, John A. 2
75(4):505-514, February 27, 2003.
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Background. Renal tubules normally show no lymphocyte infiltration, but tubulitis is a feature of renal allograft rejection with many intratubular T cells expressing CD8 and CD103 (the [alpha]E[beta]7 integrin). We investigated the development and maintenance of allospecific CD103 T cells within the tubular microenvironment.
Methods. Mixed lymphocyte cultures were supplemented with transforming growth factor (TGF)-[beta]1 to model the expression and function of CD103 observed in situ on intratubular lymphocytes. Immunocytochemical techniques were used to identify cells coexpressing CD8 and interleukin (IL)-15R[alpha], to enumerate proliferating intratubular T cells, and to quantify IL-15 expression within the tubules of control and rejection-graded transplant biopsy specimens. These results were compared with a parallel analysis of the phenotype and proliferation of allospecific T cells expanded in vitro in the presence of TGF-[beta]1 and IL-15.
Results. TGF-[beta]1 only induced the expression of adhesive CD103 after at least one cycle of alloantigen-specific cell division in vitro. In the renal allograft, a similar proportion of intratubular T cells was observed to proliferate during and after acute rejection. Tubular epithelial cells expressed IL-15 constitutively, whereas intratubular CD8 T cells expressed IL-15 receptor [alpha]. IL-15 and TGF-[beta]1 synergized to promote expansion and survival of allospecific CD8 CD103 T cells in vitro, but IL-15 down-regulated perforin expression.
Conclusions. These results suggest that activated, allospecific CD8 T cells are recruited to tubules during acute rejection where they encounter TGF-[beta], up-regulate CD103 expression, and bind E-cadherin. A proportion of these cells proliferates and is maintained in a state of low perforin expression by the combined action of TGF-[beta] and IL-15.
(C) 2003 Lippincott Williams & Wilkins, Inc.