Investigation of the lymphocyte function during tubulointerstitial injury in the native kidney

Abstract

Tubulointerstitial inflammation and fibrosis is frequently seen in patients with progressive renal failure, irrespective of the aetiology, and may represent a common pathway to renal failure. However, the role and function of tubulointerstitial lymphocytes in the pathogenesis of renal fibrosis is unknown. Using the wellcharacterised mouse model of unilateral ureteric obstruction (UUO) I determined the phenotype of infiltrating lymphocytes and by sequencing the complementaritydetermining region 3 (CDR3) of the variable β-chain examined whether there were clonal populations of T cells within UUO and normal kidney. There was a strong correlation between lymphocyte infiltration and tubulointerstitial expansion, α-SMA staining and collagen I deposition. A population of these infiltrating CD4+ and CD8+ lymphocytes also displayed the surface makers CD69 and CD44, and the nuclear proliferation marker Ki67. This suggests activation and proliferation of T cells in response to self-antigen recognition and the loss of immunological tolerance. Infiltrating T cells within UUO kidney demonstrated over expression of certain TRVβ gene segments in particular TRVβ3, suggesting a clonal population of lymphocytes. In normal and sham operated kidney over expression of T cells with the TRVβ13.2, 29 and 1 gene segments suggested populations of resident NKT cells expressing an invariant T cell receptor. On sequence analysis of the CDR3 region of infiltrating lymphocytes, large clonal populations of T cells were seen in individual UUO kidneys at 7 and 14 days after obstruction but not 28 days. These clonal populations in UUO kidney that were also in normal kidney had an identical amino acid motif within the CDR3 region. This suggests a population of T cells in normal kidney proliferate in response to injury. These lymphocytes could be a potential target for therapeutic interventions to prevent fibrosis in renal diseases that are not characteristically believed to be immune mediated.