Crry/p65, a Membrane Complement Regulatory Protein, Has Costimulatory Properties on Mouse T Cells

Abstract

It is known that certain type I membrane molecules (complement receptors type 1 and 2) belonging to the regulators of complement activation (RCA) family are involved in the regulation of B lymphocyte activation. In contrast, only GPI-anchored RCA molecules (CD55) have been described to be involved in T lymphocyte activation. In this study, we describe a novel function for the mouse RCA type I membrane protein Crry/p65 as a costimulatory molecule in CD4+ T cell activation. This is shown by increased anti-CD3-induced proliferation of CD4+ spleen T lymphocytes in the presence of the Crry/p65-specific mAb P3D2. Furthermore, Ab-induced coligation of Crry/p65 and CD3 favors IL-4 rather than IFN-γ secretion in these cells. Crry/p65 signaling was also observed regardless of additional Ca2+, protein kinase C, or CD28-mediated costimuli. Analysis of intracellular intermediaries shows that Crry/p65-CD3 coligation enhances certain TCR/CD3-mediated signals, producing increased early tyrosine phosphorylation of many substrates and enhanced activation of the mitogen-activated protein kinase, extracellular signal-related kinase. These data fit well with the association of Crry/p65 with the tyrosine kinase Lck found in T cell lysates. The epitope recognized by the mAb P3D2 interferes with the protective role of Crry/p65 on C3 deposition. The relationship between protective function and costimulation by Crry/p65 is discussed. Our results support a multifunctional role for Crry/p65 in T cells and suggest new links between the natural and adaptive immune responses.

Mouse Complement Receptor-Related Gene y/p65-Neutralized Tumor Vaccine Induces Antitumor Activity In Vivo

“…We cannot completely rule out the possibility that 5D5 induces a biological response and alters the immunogenicity of the cells via a signaling mechanism, although we consider this unlikely because the cells used for vaccination were irradiated. Transduction of viable mouse T cells by Crry/p65 has been demonstrated, although the signal from Crry/ p65 alone does not induce cell proliferation (47). Our data support the hypothesis that blocking complement-regulatory proteins on tumor cells enhances the induction, as well as the effector phase (see above), of an antitumor immune response.…”

Costimulation via CD55 on Human CD4+ T Cells Mediated by CD97

“…This is not unusual, because a similar effect has been observed for other GPI-anchored molecules, like murine Thy-1 (32), and non-GPI-anchored complement regulatory proteins, like the murine Crry (25). For CD55 in particular, cross-linking of CD55 Abs was previously shown to be an essential prerequisite for exerting costimulation (15).…”

“…This was analyzed, as previously described (23,25,26), by measurement of C3b deposition on the cells, in the presence of a CD55 neutralizing mAb, 791T/36, and a known nonneutralizing mAb, BRIC 220 (23), which binds to SCR1 on CD55, a domain not involved in complement regulation (27). Purified CD4 ϩ T cells were incubated with the mAbs and isotype-matched controls (IgG2b and IgG1, respectively) for 1 h and then exposed to 10% of fresh human serum for 2 h. Staining for C3b showed no deposition in the absence of fresh serum (data not shown), whereas there was a basal deposition on cells alone (Fig.…”

A Novel Chicken Membrane-Associated Complement Regulatory Protein: Molecular Cloning and Functional Characterization

“…The SCR protein CR2 is expressed on B cells in humans and mice, and forms a complex with CD19 and TAPA-1 to signal the cells (6 -8). The other SCR proteins Crry and MCP can serve as costimulators for proliferation of T cells and lead to secretion of IL-4 (36,37). In addition, most C regulatory proteins are expressed at high levels in the testicular germ cells in mammals (18,38), and their function may be related to fertilization (39,40).…”