TIRC7 Inhibits T Cell Proliferation by Modulation of CTLA-4 Expression

Abstract

Ab targeting of TIRC7 has been shown previously to inhibit T cell proliferation and Th1 lymphocyte-associated cytokine production. In this study, we demonstrate that Ab targeting of TIRC7 induces early cell surface expression of CTLA-4. The majority of stimulated CD4+ and CD8+ human T cells coexpress CTLA-4 and TIRC7. Similar to CTLA-4, TIRC7 rapidly accumulates at the site of Ag adhesion upon T cell activation. TIRC7 seems to colocalize with CTLA-4 in human T cells, and both molecules are associated with clathrin-coated vesicles, indicating they share intracellular transport systems. Moreover, Ab targeting of TIRC7 results in an early activation of CTLA-4 transcription. The inhibition of cell proliferation mediated by TIRC7 is dependent on CTLA-4 expression because the TIRC7-mediated inhibitory effects on cell proliferation and cytokine expression are abolished by Ab blockade of CTLA-4. Splenocytes obtained from CTLA-4-deficient mice are not responsive to TIRC7 Ab targeting. Thus, TIRC7 acts as an upstream regulatory molecule of CTLA-4 expression.

CTLA-4 trafficking and surface expression

“…Consistently, TIRC7 À/À T cells exhibited increased proliferation and expression of IL-2, interferon g (IFN-g) and IL-4 [68,69]. Co-localisation of TIRC7 and CTLA-4 occurred close to the site of TCR engagement, but no direct interaction of TIRC7 and CTLA-4 was shown [70]. Therefore, the activation-induced transmembrane protein TIRC7 might be involved in CTLA-4 expression via a yet unknown mechanism.…”

FOXP3, CBLBandITCHgene expression and cytotoxic T lymphocyte antigen 4 expression on CD4+CD25high T cells in multiple sclerosis

“…The FoxP3 molecule is a transcription factor that controls the expression of genes responsible for the regulatory phenotype of CD25 [46] -also known as TIRC7 -which is crucially involved in the expression and intracellular trafficking of CTLA-4 to the T cell surface [47,48].…”

Antithymocyte globulin combined with cyclosporine A down-regulates T helper 1 cells by modulating T cell immune response cDNA 7 in aplastic anemia

“…It has been shown to be essential in T cell activation [9,10]. Further studies demonstrated that the antibody against TIRC7 could significantly inhibit the expression of interleukin (IL)-2 and interferon (IFN)-c, without affecting the expression of IL-4, indicating the critical role of TIRC7 in T helper (Th) 1 cells [11].…”

“…T cells could provide the suppressive activity in the intestinal inflammation and represent IL-10-secreting Tregs. In addition, TIRC7 was reported to inhibit T cell proliferation by modulation of CTLA-4 expression [10]. Meanwhile, some studies have also documented the importance of TIRC7 on some autoimmune diseases [16]; nevertheless, there were few relevant reports of TIRC7 in hematological diseases.…”