title: Expansion of Tfh-like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88-deficient mice.
abstract: The role of TLR signaling in linking the innate and adaptive immune systems has been a controversial issue that remains to be solved. Here, we determined whether MyD88-dependent TLR signals are required for the generation of B-cell responses during chronic Salmonella infection. Oral administration of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine (RASV) strain in MyD88(-/-)  mice resulted in chronic infection. Infection was accompanied by enlarged germinal centers and hypergammaglobulinemia with anti-double-stranded DNA (dsDNA)-specific Ab in sera, and the deposition of immune complexes in the kidneys, suggesting onset of autoimmunity. CD4(+)  T cells expressing PD-1, CXCR5, ICOS, and IL-21 were dramatically increased in chronically infected mice, indicating the expansion of follicular helper T (Tfh)-like cells. Of note, the depletion of CD4(+)  T cells completely blocked the generation of polyclonal IgG Ab in sera after oral RASV challenge. Inflammatory myeloid cells expressing CD11b and Gr-1 accumulated in high numbers in the spleen of MyD88(-/-)  mice. Interestingly, the blockade of PD-1 or ICOS significantly reduced the hypergammaglobulinemia and dsDNA-specific autoantibody production. Overall, these results suggest that Tfh-like cells in chronic bacterial infection trigger autoimmune hypergammaglobulinemia in a PD-1- and ICOS-dependent manner.
authors: Mucosal Immunology Section, Laboratory Science Division, International Vaccine Institute, Seoul, Korea.
authors: Hyun-Jeong
authors: HJ
authors: Ko
authors: Hyungjun
authors: H
authors: Yang
authors: Jin-Young
authors: JY
authors: Yang
authors: Sang-Uk
authors: SU
authors: Seo
authors: Sun-Young
authors: SY
authors: Chang
authors: Je Kyung
authors: JK
authors: Seong
authors: Mi-Na
authors: MN
authors: Kweon
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D006942:Hypergammaglobulinemia / Q000276:immunology / Q000382:microbiology*; D007074:Immunoglobulin G / Q000097:blood; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000191:economics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054380:Receptors, CXCR5 / Q000235:genetics / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D000943:Antigens, Differentiation; C513179:CXCR5 protein, mouse; C556694:Icos protein, mouse; D007074:Immunoglobulin G; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D054380:Receptors, CXCR5; D012313:RNA; D000098546:Interleukin-21