Deficiency of antigen-specific B cells results in decreased Trypanosoma cruzi systemic but not mucosal immunity due to CD8 T cell exhaustion.

Vaccines against mucosally invasive, intracellular pathogens must induce a myriad of immune responses to provide optimal mucosal and systemic protection, including CD4(+) T cells, CD8(+) T cells, and Ab-producing B cells. In general, CD4(+) T cells are known to provide important helper functions for both CD8(+) T cell and B cell responses. However, the relative importance of CD4(+) T cells, CD8(+) T cells, and B cells for mucosal protection is less clearly defined. We have studied these questions in detail using the murine model of Trypanosoma cruzi infection. Despite our initial hypothesis that mucosal Abs would be important, we show that B cells are critical for systemic, but not mucosal, T. cruzi protective immunity. B cell-deficient mice developed normal levels of CD8(+) effector T cell responses early after mucosal T. cruzi infection and T. cruzi trans-sialidase vaccination. However, after highly virulent systemic challenge, T. cruzi immune mice lacking T. cruzi-specific B cells failed to control parasitemia or prevent death. Mechanistically, T. cruzi-specific CD8(+) T cells generated in the absence of B cells expressed increased PD-1 and Lag-3 and became functionally exhausted after high-level T. cruzi systemic challenge. T. cruzi immune serum prevented CD8(+) T cell functional exhaustion and reduced mortality in mice lacking B cells. Overall, these results demonstrate that T. cruzi-specific B cells are necessary during systemic, but not mucosal, parasite challenge.