Pathological and clinical correlates of FOXP3+ cells in renal allografts during acute rejection

Am J Transplant. 2007 Apr;7(4):914-22. doi: 10.1111/j.1600-6143.2006.01704.x. Epub 2007 Feb 7.


The localization and significance of regulatory T cells (Treg) in allograft rejection is of considerable clinical and immunological interest. We analyzed 80 human renal transplant biopsies (including seven donor biopsies) with a double immunohistochemical marker for the Treg transcription factor FOXP3, combined with a second marker for CD4 or CD8. Quantitative FOXP3 cell counts were performed and analyzed for clinical and pathologic correlates. FOXP3(+) cells were present in the interstitium in acute cellular rejection (ACR) type I and II, at a greater density than in acute humoral rejection or CNI toxicity (p < 0.01). Most FOXP3(+) cells were CD4(+) (96%); a minority expressed CD8. FOXP3(+)CD4(+) cells were concentrated in the tubules (p < 0.001), suggesting a selective attraction or generation at that site. Considering only patients with ACR, a higher density of FOXP3(+) correlated with HLA class II match (p = 0.03), but paradoxically with worse graft survival. We conclude that infiltration of FOXP3(+) cells occurs in ACR to a greater degree than in humoral rejection, however, within the ACR group, no beneficial effect on outcome was evident. Tregs concentrate in tubules, probably contributing to FOXP3 mRNA in urine; the significance and pathogenesis of 'Treg tubulitis' remains to be determined.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / analysis
  • Biopsy
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / pathology
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Graft Rejection / pathology*
  • Humans
  • Immunohistochemistry
  • Kidney Transplantation / pathology*
  • RNA, Messenger / genetics
  • RNA, Messenger / urine
  • Retrospective Studies
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Transplantation, Homologous / pathology
  • Treatment Outcome


  • Antigens, CD
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • RNA, Messenger