Tubulitis in renal allograft rejection: role of transforming growth factor-beta and interleukin-15 in development and maintenance of CD103+ intraepithelial T cells.
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 alphaEbeta7 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)-beta1 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)-15Ralpha, 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-beta1 and IL-15.


RESULTS
TGF-beta1 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-beta1 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.
Wong
Wai Keong
WK
Applied Immunobiology Group, Department of Surgery, Medical School, University of Newcastle upon Tyne NE2 4HH, UK.
Robertson
Helen
H
Carroll
Helen P
HP
Ali
Simi
S
Kirby
John A
JA
D015703:Antigens, CD / Q000032:analysis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002461:Cell Line, Transformed; D002908:Chronic Disease; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D039001:Integrin alpha Chains / Q000032:analysis; D019409:Interleukin-15 / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D007684:Kidney Tubules / Q000166:cytology / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D009395:Nephritis, Interstitial / Q000276:immunology*; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology*; D014184:Transplantation, Homologous
D015703:Antigens, CD; D039001:Integrin alpha Chains; D019409:Interleukin-15; D016212:Transforming Growth Factor beta; C091367:alpha E integrins