MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses.
Bacteremia is one of the leading causes of death by infectious disease. To understand the immune mechanisms required for the rapid control of bacteremia, we studied Borrelia hermsii, a bacterial pathogen that colonizes the blood stream of humans and rodents to an extremely high density. A T cell-independent IgM response is essential and sufficient for controlling B. hermsii bacteremia. Mice deficient in Bruton's tyrosine kinase (Btk), despite their known defect in BCR signaling, generated B. hermsii-specific IgM and resolved bacteremia, suggesting that an alternative activation or costimulatory pathway remained functional for T cell-independent B cells in Btk(-/-) mice. B. hermsii contains putative ligands for TLRs, and we found that mice deficient in TLR1, TLR2, or the TLR adaptor MyD88 generated anti-B. hermsii IgM with delayed kinetics and suffered more severe episodes of bacteremia. In striking contrast to the anti-B. hermsii IgM response in mice deficient only in Btk, mice deficient in both Btk and MyD88 were entirely incapable of generating B. hermsii-specific Ab or resolving bacteremia. The response to a T cell-dependent model Ag was unaffected in Btk(-/-) x MyD88(-/-) mice. These results suggest that MyD88 specifically promotes T cell-independent BCR signaling and that, in the absence of Btk, this TLR-mediated stimulation is a required component of this signal.
Alugupalli
Kishore R
KR
Department of Microbiology and Immunology and Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA. kishore.alugupalli@mail.jci.tju.edu
Akira
Shizuo
S
Lien
Egil
E
Leong
John M
JM
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001898:Borrelia / Q000276:immunology; D001899:Borrelia Infections / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D007375:Interleukin-1; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology
D000907:Antibodies, Bacterial; D007075:Immunoglobulin M; D007375:Interleukin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011947:Receptors, Antigen, B-Cell; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse