Novel function of perforin in negatively regulating CD4+ T cell activation by affecting calcium signaling

Abstract

Perforin is a pore-forming protein engaged mainly in mediating target T cell death and is employed by cytotoxic T lymphocytes (CTLs) and natural killer cells. However, whether it also plays a role in conventional CD4 + T cell function remains unclear. Here we report that in perforin-deficient (PKO) mice, CD4 + T cells are hyperproliferative in response to T cell receptor (TCR) stimulation. This feature of hyperproliferation is accompanied by the enhancement both in cell division and in IL-2 secretion. It seems that the perforin deficiency does not influence T cell development in thymus spleen and lymph node. In vivo, perforin deficiency results in increased antigen-specific T cell proliferation and antibody production. Furthermore, PKO mice are more susceptible to experimental autoimmune uveitis. To address the molecular mechanism, we found that after TCR stimulation, CD4 + T cells from PKO mice display an increased intracellular calcium flux and subsequently enhance activation of transcription factor NFAT1. Our results indicate that perforin plays a negative role in regulating CD4 + T cell activation and immune response by affecting TCR-dependent Ca 2+ signaling.

Identification of unique proteins in vitreous fluid of patients with noninfectious uveitis

“…Apart from this, we found repulsive guidance molecule, which inhibits leucocyte migration and reduces inflammation (Demicheva et al 2015). In contrast, perforin can negatively regulate CD4 + T-cell activation and immune response (Bi et al 2009). In addition, alpha-1-acid glycoprotein 1 (Dalin 2015), histone-lysine N-methyltransferase (Yamashita et al 2006) and chitinase-3-like protein 1 (Kamba et al 2013) have also been reported to take part in inflammation.…”

“…Immunoregulation and autoimmunity play an important role in the pathogenesis of uveitis. In contrast, perforin can negatively regulate CD4 + T-cell activation and immune response (Bi et al 2009). Monoclonal antibody blockade ICAM-2 causes the recruitment of inflammatory cells in the anterior chamber of eye during Pseudomonas aeruginosa infection (Hobden 2003).…”