Lymphocytes control early onset of innate inflammation but are dispensable for its resolution. (A,B) Although inflammation doubled in RAG1^−/− during the onset phase in response to zymosan, coincident with (C) an imbalance of IL-10 versus TNFα, inflammation normalized with that of wild-type mice from 24 hours onward, suggesting no role for lymphocytes in actively bringing about resolution (ie, clearing PMNs or macrophages). (D) However, RAG1^−/− and wild-type mice were injected with GBS during resolution (48 hours after zymosan injection), resulting in enhanced leukocyte accumulation in RAG1^−/− but not wild-type mice 24 hours later. (E) This was associated with reduced bacterial colonization in plasma but (F) increased mortality in RAG1^−/− mice as a result of the concomitant hyperinflammatory response. We therefore argue that lymphocytes are not required for bringing about resolution and propose that their reappearance hails the end of the inflammatory event and an attempt at restorative physiology. Their role in this setting is in protecting against secondary infection or injury with B cells, CD4⁺/CD25⁺ cells, and γ/δ T cells as well as NK cells playing a likely role in this setting. n = 6 to 8 animals per group, with experiments repeated on 2 separate occasions to confirm original findings. *P ≤ .05; **P ≤ .01, as determined by ANOVA, followed by Bonferroni t test, with data expressed as means plus or minus SEM.