title: Neonatal exposure to antigen induces a defective CD40 ligand expression that undermines both IL-12 production by APC and IL-2 receptor up-regulation on splenic T cells and perpetuates IFN-gamma-dependent T cell anergy.
abstract: T cell deletion and/or inactivation were considered the leading mechanisms for neonatal tolerance. However, recent investigations have indicated that immunity develops at the neonatal stage but evolves to guide later T cell responses to display defective and/or biased effector functions. Although neonatal-induced T cell modulation provides a useful approach to suppress autoimmunity, the mechanism underlying the biased function of the T cells remains unclear. In prior studies, we found that exposure of newborn mice to Ig-PLP1, a chimera expressing the encephalitogenic proteolipid protein (PLP) sequence 139-151, induced deviated Th2 lymph node cells producing IL-4 instead of IL-2 and anergic splenic T cells that failed to proliferate or produce IFN-gamma yet secreted significant amounts of IL-2. However, if assisted with IFN-gamma or IL-12, these anergic splenic T cells regained full responsiveness. The consequence of such biased/defective T cells responses was protection of the mice against experimental allergic encephalomyelitis. In this study, investigations were performed to delineate the mechanism underlying the novel form of IFN-gamma-dependent splenic anergy. Our findings indicate that CD40 ligand expression on these splenic T cells is defective, leading to noneffective cooperation between T lymphocytes and APCs and a lack of IL-12 production. More striking, this cellular system revealed a requirement for IL-2R expression for CD40 ligand-initiated, IL-12-driven progression of T cells into IFN-gamma production.
authors: Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA.
authors: B
authors: B
authors: Min
authors: K L
authors: KL
authors: Legge
authors: J J
authors: JJ
authors: Bell
authors: R K
authors: RK
authors: Gregg
authors: L
authors: L
authors: Li
authors: J C
authors: JC
authors: Caprio
authors: H
authors: H
authors: Zaghouani
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D007106:Immune Sera / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D007106:Immune Sera; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C435023:myelin proteolipid protein (139-151); D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma