MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2

McCarthy, Mary K.; Reynoso, Glennys V.; Winkler, Emma S.; Mack, Matthias; Diamond, Michael S.; Hickman, Heather D.; Morrison, Thomas E.

Total lymphocyte numbers in the dLN were increased in the dLN of Nos2 -/and Nox2 -/mice compared with WT mice following pathogenic CHIKV infection. In addition, and in contrast to WT mice, pathogenic CHIKV infection had minimal effects on the organization of B cell follicles and the T cell zone in the dLN of Nos2 -/and Nox2 -/mice. Flow cytometric analysis revealed that monocytes, but not neutrophils, upregulated iNOS expression following entry into the dLN. During LCMV infection of mice, monocytes infiltrating the dLN induced apoptosis in virus-specific and bystander B cells in a Nos2-dependent manner [5] . Studies with LCMV also observed B cell depletion in lymphoid tissue, however, individual roles for Nos2 [55] or Gr-1 + cells [56] were not defined. In contrast to LCMV infection, extensive lymphocyte death or an increase in apoptotic lymphocytes does not occur in the dLN following pathogenic CHIKV infection [23] , suggesting that the infiltrating monocytes do not impair B cell responses by inducing death of lymphocytes. Additionally, lymphocyte numbers were restored only partially in mice deficient for Nos2 or Nox2, suggesting that the combined action of Nos2 and Nox2 or other monocyte and/or neutrophil-derived factors contribute to the impairment of naive lymphocyte accumulation and disruption of LN organization. Depletion of either neutrophils or monocytes alone did not restore total lymphocyte numbers in the dLN, indicating that influx of either cell type is sufficient to prevent accumulation of naïve lymphocytes. Although the improved dLN organization and lymphocyte accumulation observed in Nos2deficient mice could be ascribed to lack of iNOS expression uniquely in monocytes, the mechanism(s) by which neutrophils impair lymphocyte accumulation and disrupt dLN architecture remain to be determined.