Expansion of Tfh-like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88-deficient mice.

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.