CD3 and Immunoglobulin G Fc Receptor Regulate Cerebellar Functions

Abstract

The immune and nervous systems display considerable overlap in their molecular repertoire. Molecules originally shown to be critical for immune responses also serve neuronal functions that include normal brain development, neuronal differentiation, synaptic plasticity, and behavior. We show here that Fc␥RIIB, a low-affinity immunoglobulin G Fc receptor, and CD3 are involved in cerebellar functions. Although membranous CD3 and Fc␥RIIB are crucial regulators on different cells in the immune system, both CD3 and Fc␥RIIB are expressed on Purkinje cells in the cerebellum. Both CD3-deficient mice and Fc␥RIIB-deficient mice showed an impaired development of Purkinje neurons. In the adult, rotarod performance of these mutant mice was impaired at high speed. In the two knockout mice, enhanced paired-pulse facilitation of parallel fiberPurkinje cell synapses was shared. These results indicate that diverse immune molecules play critical roles in the functional establishment in the cerebellum.Some molecules originally shown to be critical for immune responses, such as the major histocompatibility complex (MHC) class I molecules, CD3, and semaphorin 7A (3,8,15,23), also serve neuronal functions. Based on studies of mutant mice, CD3 proved critical for the development of lateral geniculate nucleus (LGN) and long-term synaptic plasticity in the adult hippocampus (3,8).In the immune system, CD3 subunits are expressed on T cells. The T-cell receptor (TCR)-CD3 complex recognizing specific antigens bound to MHC present on antigen-presenting cells (APCs) is composed of a TCR heterodimer and CD3 polypeptides organized as dimers. The cell-cell interaction between APCs and T cells is known as an immunological synapse (5) in the mature immune system. In ␣␤ T cells, when the TCR interacts with the antigen/MHC complex, it transmits information to a signal-transducing complex consisting of two CD3 subunit dimers, CD3ε-CD3␥ and CD3ε-CD3␦, and the CD3-CD3 homodimer (10). Among CD3 subunits, CD3 is a crucial subunit having three immunoreceptor tyrosine-based activation motifs (ITAMs), whereas the remaining subunits have one ITAM (25). Tyrosine residues within these motifs are phosphorylated by src family tyrosine kinases, and then Src homology 2-containing proteins, including the tyrosine kinase ZAP70, participate in signaling (13). The signaling in ␥␦ TCRs is different from that in ␣␤ TCRs. Most ␥␦ TCRs lack CD3␦, and signal transduction by ␥␦ TCR is superior to that by ␣␤ TCR, as measured by its ability to induce calcium mobilization, extracellular signal-regulated kinase activation, and cellular proliferation (6).Fc␥RIIB is a low-affinity membrane receptor for immune complexes broadly distributed on hematopoietic cells, such as B cells, mast cells, basophils, macrophages, eosinophils, neutrophils, dendritic cells, and Langerhans cells. Fc␥RIIB negatively regulates B-cell receptor-induced signaling in B cells via the inhibitory immunoreceptor tyrosine-based inhibition motif in its cytoplasmic domain (24,30). Coengagement of the B-cell rece...

The Signaling Adaptor Protein CD3ζ Is a Negative Regulator of Dendrite Development in Young Neurons

“…The cerebral expression of the four CD3 subunits raised the possibility that a kind of CD3 complex may exist in the brain similarly as in the immune system. However, CD3 mRNA was not detected in the cerebellum (Nakamura et al, 2007), and we were not able to detect CD3 at the protein level in forebrain samples (data not shown). Thus CD3 appeared to be expressed in distinct brain regions different from those for CD3, -␥, and -␦, suggesting that CD3 may function independently from the other CD3 subunits, as reported in NK cells (Lanier, 2001).…”

“…The CD3, -␥ and -␦ have all been detected in the cerebellum and CD3-deficient mice, in which CD3-␥ and CD3-␦ protein levels are also reduced, showed an impaired neuronal architecture of Purkinje neurons (Nakamura et al, 2007). The cerebral expression of the four CD3 subunits raised the possibility that a kind of CD3 complex may exist in the brain similarly as in the immune system.…”

Major Histocompatibility Complex I in Brain Development and Schizophrenia

“…Although obligate components of the TCR complex are non-functional or missing in the brain (55), TCR co-receptors, including CD3ζ and CD3ε, are present in the rodent and feline CNS (56–58). It remains unknown whether or how MHCI interacts with these co-receptors.…”

Prolyl Isomerase Pin1 Regulates Neuronal Differentiation via β-Catenin

“…The primary antibodies used were goat anti-Brn1 (Santa Cruz Biotechnology, Santa Cruz, CA), anti-Brn2 (Santa Cruz), and anti-BLBP (Santa Cruz), mouse antireelin (Santa Cruz), goat antinestin (Santa Cruz), goat anti-GFAP (Santa Cruz), mouse anti-PSD95 (BD Biosciences), mouse antibromodeoxyuridine (anti-BrdU) (BD Biosciences), rat anti-BrdU (Serotec, Oxford, United Kingdom), mouse anti-␤-catenin (BD Biosciences), rabbit anti-␤-catenin (Cell Signaling, Danvers, MA), mouse anti-Pax6 (Abcam), guinea pig antidoublecortin (anti-DCX) (Millipore), mouse anti-␤III tubulin (Millipore), rabbit anti-␤III tubulin (TUJ1) (Covance, Princeton, NJ), mouse anti-Pin1 (35), rabbit anti-Pin1 (35), rat anti-CTIP2 (Abcam, Cambridge, MA), and rabbit anti-Tbr2 (14) (kindly provided by Robert F. Hevner) antibodies. Immunofluorescence staining and immunohistochemistry of the mouse brain and cultured cells were done essentially as described previously (35,56,57,59), and samples were visualized with a confocal microscope (Zeiss LSM510). The intensities of BrdU-, DCX-, Pax6-, Tbr2-, Brn1-, and Brn2-positive signals were counted within the same area for WT and Pin1 KO mice, with WT control levels being defined as 100% (n ϭ 2 to 7 per group).…”