ABSTRACT
Dectin-1 is an innate antifungal C-type lectin receptor necessary for protective antifungal immunity. We recently discovered that Dectin-1 is involved in controlling fungal infections of the gastrointestinal (GI) tract, but how this C-type lectin receptor mediates these activities is unknown. Here, we show that Dectin-1 is essential for driving fungal-specific CD4(+) T-cell responses in the GI tract. Loss of Dectin-1 resulted in abrogated dendritic cell responses in the mesenteric lymph nodes (mLNs) and defective T-cell co-stimulation, causing substantial increases in CD4(+) T-cell apoptosis and reductions in the cellularity of GI-associated lymphoid tissues. CD8(+) T-cell responses were unaffected by Dectin-1 deficiency. These functions of Dectin-1 have significant implications for our understanding of intestinal immunity and susceptibility to fungal infections.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Candida albicans/immunology , Candidiasis/immunology , Gastrointestinal Tract/immunology , Lectins, C-Type/immunology , Adoptive Transfer , Animals , Apoptosis/immunology , CD4-Positive T-Lymphocytes/microbiology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/transplantation , CD8-Positive T-Lymphocytes/microbiology , CD8-Positive T-Lymphocytes/pathology , Candidiasis/genetics , Candidiasis/microbiology , Candidiasis/pathology , Cell Survival/immunology , Female , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/pathology , Gene Expression , Lectins, C-Type/deficiency , Lectins, C-Type/genetics , Lymph Nodes/immunology , Lymph Nodes/microbiology , Lymph Nodes/pathology , Lymphocyte Activation , Mesentery/immunology , Mesentery/microbiology , Mesentery/pathology , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Gα13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt's lymphoma and DLBCL.
