Abstract
In mice, neonatally-developing, self-reactive B-1 cells generate steady levels of natural antibodies throughout life. B-1 cells can, however, also rapidly respond to infections with increased local antibody production. The mechanisms regulating these two seemingly very distinct functions are poorly understood, but have been linked to expression of CD5, an inhibitor of BCR-signaling. Here we demonstrate that TLR-mediated activation of CD5+ B-1 cells induced the rapid reorganization of the IgM-BCR complex, leading to the eventual loss of CD5 expression, and a concomitant increase in BCR-downstream signaling, both in vitro and in vivo after infections of mice with influenza virus and Salmonella typhimurium. Both, initial CD5 expression and TLR-mediated stimulation, were required for the differentiation of B-1 cells to IgM-producing plasmablasts after infections. Thus, TLR-mediated signals support participation of B-1 cells in immune defense via BCR-complex reorganization.
Highlights
During lymphocyte development-antigen binding by the TCR and BCR results in negative selection, leading to the removal of strongly self-reactive lymphocytes from the T and B cell repertoire
Chimeric mice reconstituted with either allotypically-marked CD5 + or CD5- B-1 cells showed that only CD5+ B-1 cells were responding in vivo to influenza infection with migration from the pleural cavity to the draining mediastinal lymph nodes (MedLN) in a Type I IFN-dependent process, where they differentiated into IgM-secreting cells (Choi and Baumgarth, 2008; Waffarn et al, 2015)
We previously identified three populations of cells involved in natural IgM secretion: CD5+ B-1 cells, CD5- B-1 cells, and plasma cells, the latter are CD19- and CD138/Blimp-1+ (Savage et al, 2017) and B-1-derived (B-1PC) (Savage et al, 2017)
Summary
During lymphocyte development (self)-antigen binding by the TCR and BCR results in negative selection, leading to the removal of strongly self-reactive lymphocytes from the T and B cell repertoire. Natural IgM production is not stochastic, but instead likely driven by expression of self-antigens This was demonstrated by Hayakawa et al, who showed a lack of anti-Thy-1 self-reactive IgM antibodies in the serum of Thy-1-deficient but not Thy-1 expressing mice (Hayakawa et al, 1999; Hayakawa et al, 2003), as well as repertoire studies by Yang et al, which showed selective and extensive clonal expansion of certain CD5 + B-1 cell clones during the first 6 months of life, including in germfree mice (Yang et al, 2015). The reasons for the apparent different behaviors of CD5+ and CD5B-1 cells in the various infectious disease models are unexplained It is unclear how B-1 cells expressing CD5 can participate in antigen-specific immune responses. Mediated signals support participation of B-1 cells in immune defense via BCR-complex reorganization, linking innate and adaptive antigen-recognition by B-1 cells
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