CD4+ T Lymphocytes, Especially Th2 Cells, Contribute to the Progress of Renal Fibrosis

Abstract

Background: Renal tubulointerstitial fibrosis is the final common stage of renal failure. CD4+ T lymphocyte recruitment and activation after injury could be the very important early event that mediates the onset of renal fibrogenesis. But the role of CD4+ T lymphocytes in renal fibrosis is controversial and its cellular mechanism needs to be further investigated. Methods: Biopsy specimens were from patients with minimal-change or IgA nephropathy. Mouse renal fibrosis was induced by unilateral ureteral obstruction (UUO). CD4+ T lymphocytes of wild BALB/c mice were depleted with anti-CD4 antibody. BALB/c Nu/Nu mice were reconstituted with polarized Th1 or Th2 cells by tail vein injection. Results: Our study demonstrated that massive CD4+ T lymphocytes infiltrated fibrotic kidneys of patients. The depletion of CD4+ T lymphocytes inhibited UUO-induced mouse renal fibrosis. In the process of UUO-induced renal fibrosis, the ratios of Th2/Th1 increased with time. Results have also shown that Th2-reconstituted mice developed renal fibrosis more easily than Th1-reconstituted mice, which manifested by interstitial expansion and collagen deposition, higher expression of α-SMA and vimentin and increased expression of fibronectin, TGF-β and collagen I. We also found that CD4+ T cells from Th1-reconstitued mice tended to secrete IL-4 and IL-13 Th2-like cytokines. Conclusion: In conclusion, our study demonstrated the importance of CD4+ T lymphocytes in renal fibrosis and gave the first direct evidence that Th2 cells play a pivotal role in UUO-induced renal fibrosis. Inhibition of CD4+ T lymphocyte differentiation to Th2 would be a potential therapeutic intervention to prevent renal fibrosis.

Transcriptional regulation of CD4 gene expression in porcine kidney epithelial cells by virus-like double-stranded RNA and DNA methyltransferase inhibitor

“…T lymphocytes that express the CD4 marker, primarily of the CD3 + T lymphocyte phenotype, have been shown to be activated during acute kidney injury (Lie et al, 2012). Recruitment and activation of CD4 + T lymphocytes after kidney injury could be the very important early event that mediates the onset of renal fibrogenesis (Liu et al, 2012). The kidney is one of the target tissues of porcine pseudorabies virus (PRV), Africa swine fever virus (ASFC) and classical swine fever virus (CSFV) (Flori et al, 2008;Sun et al, 2008;Wei and Qing, 2008).…”

Depletion of CD8+ T Cells Exacerbates CD4+ T Cell–Induced Monocyte-to-Fibroblast Transition in Renal Fibrosis

“…injection of CD4 mAb (RM4-5, BioLegend, San Diego, CA) as described (31). Briefly, RM4-5 (3 mg/kg) was administered for 1 d before and on the day of UUO and tissues harvested on day 7.…”

“…Profibrotic IL-4 is mainly produced by CD4 + Th2 cells, and antifibrotic IFN-g is primarily produced by CD4 + Th1 cells or CD8 + T cells in the regulation of fibrosis after injury (29,30). Depletion of CD4 protects against renal fibrosis, whereas adoptive transfer of CD4 + (but not CD8 + ) T cells into lymphocyte-deficient mice restores fibrosis (11,26,31). Moreover, reconstitution of lymphocyte-deficient mice with Th2 cells enhances fibrosis to a greater degree than reconstitution with Th1 cells, identifying Th2 cells as a therapeutic target for renal fibrosis (31).…”

“…Depletion of CD4 protects against renal fibrosis, whereas adoptive transfer of CD4 + (but not CD8 + ) T cells into lymphocyte-deficient mice restores fibrosis (11,26,31). Moreover, reconstitution of lymphocyte-deficient mice with Th2 cells enhances fibrosis to a greater degree than reconstitution with Th1 cells, identifying Th2 cells as a therapeutic target for renal fibrosis (31). In addition, T cells might participate in renal fibrosis by regulating the differentiation of circulating fibroblast precursor cells derived from the bone marrow (11).…”

Links between coagulation, inflammation, regeneration, and fibrosis in kidney pathology

“…42 Bone marrow progenitor cells and leukocytes contribute to mesenchymal healing of the kidney as evidenced by interventions that inhibit leukocyte recruitment that can prevent directly or indirectly renal fibrogenesis. [147][148][149][150][151][152] More specifically, inhibition, deletion, or depletion of alternatively activated macrophages reduces renal fibrogenesis. [153][154][155][156] Ly6G+ collagen-producing 'fibrocytes' from the bone marrow invade the kidney via CCL21-CCR7 and contribute to local collagen secretion.…”