TIRC7 Deficiency Causes In Vitro and In Vivo Augmentation of T and B Cell Activation and Cytokine Response

Abstract

The membrane protein T cell immune response cDNA 7 (TIRC7) was recently identified and was shown to play an important role in T cell activation. To characterize the function of TIRC7 in more detail, we generated TIRC7-deficient mice by gene targeting. We observed disturbed T and B cell function both in vitro and in vivo in TIRC7−/− mice. Histologically, primary and secondary lymphoid organs showed a mixture of hypo-, hyper-, and dysplastic changes of multiple lymphohemopoietic compartments. T cells from TIRC7−/− mice exhibited significantly increased proliferation and expression of IL-2, IFN-γ, and IL-4 in response to different stimuli. Resting T cells from TIRC7−/− mice exhibited decreased CD62L, but increased CD11a and CD44 expression, suggesting an in vivo expansion of memory/effector T cells. Remarkably, activated T cells from TIRC7−/− mice expressed lower levels of CTLA-4 in comparison with wild-type cells. B cells from TIRC7-deficient mice exhibited significantly higher in vitro proliferation following stimulation with anti-CD40 Ab or LPS plus IL-4. B cell hyperreactivity was reflected in vivo by elevated serum levels of various Ig classes and higher CD86 expression on B cells. Furthermore, TIRC7 deficiency resulted in an augmented delayed-type hypersensitivity response that was also reflected in increased mononuclear infiltration in the skin obtained from TIRC7-deficient mice food pads. In summary, the data strongly support an important role for TIRC7 in regulating both T and B cell responses.

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

“…This effect was associated with hyporesponsiveness of the lymphocytes and an enhanced up-regulation of CTLA-4 expression on the cell surface (12). The latter observation of CTLA-4 up-regulation is in agreement with a recent finding that in lymphocytes obtained from TIRC7-deficient mice, the intracellular and cell surface expression of CTLA-4 is markedly reduced compared with wild-type lymphocytes before and after activation, whereas no differences are observed for either CD28 or CD40L expression (13).…”

Direct recruitment of H+-ATPase from lysosomes for phagosomal acidification

“…Although targeted mutations, as well as natural mutations in mouse Tcirg1 have been characterized previously (Li et al, 1999;Scimeca et al, 2000;Utku et al, 2004), the defects in macrophage function have not been described. Tcirg1, the current official nomenclature for the structural gene of V-ATPase a3 subunit, stands for 'T-cell, immune regulator 1', reflecting the fact that this molecule was identified during studies on a T-cell activation signaling (Utku et al, 1998).…”

Characterization of IL-10-Secreting T Cells Derived from Regulatory CD4+CD25+ Cells by the TIRC7 Surface Marker

“…Targeting of TIRC7 with specific Abs causes inhibition of Th1 cytokine secretion in human lymphocytes (12). In contrast, TIRC7-deficient mice show an enhanced T cell proliferation and Th1 cytokine secretion, suggesting a role for TIRC7 in regulating T cell response (43). However, the role of TIRC7 in IL-10-secreting CD25 low TIRC7 ϩ cells remains to be determined.…”