Tertiary lymphoid structures (TLS) are triggered by persistent bronchopulmonary infection with S. aureus but their roles remain elusive. The present study sought to examine the effects of B and/or T cell depletion on S. aureus infection and TLS development (lymphoid neogenesis) in mice.C57Bl/6 mice were pretreated with (1) an anti-CD20 mAb (B cell depletion) or (2) an anti-CD4 and/or an anti-CD8 mAbs (T cell depletion) or (3) a combination of anti-CD20, anti-CD4 and anti-CD8 mAbs (combined B and T cell depletion) or (4) with isotype control mAbs. After lymphocyte depletion, mice were infected by intratracheal instillation of agarose beads containing S. aureus (106 CFU/mouse). Fourteen days later, bacterial load and lung inflammatory cell infiltration were assessed by cultures and immunohistochemistry, respectively.Fourteen days after S. aureus-bead instillation, lung bacterial load was comparable between control and lymphocyte-depleted mice. While TLS were observed in the lungs of infected mice pretreated with control mAbs, these structures were disorganised or abolished in the lungs of lymphocyte-depleted mice. The absence of CD20+ B lymphocytes had no effect on CD3+ T lymphocyte infiltration, whereas CD4+/CD8+ T-cell depletion markedly reduced CD20+ B cell infiltration. Depletion of CD4+ or CD8+ T cells separately had limited effect on B cell infiltration but lead to the absence of germinal center.TLS disorganisation is not associated with loss of infection control in mice persistently infected with S. aureus.