Different Lymphocyte Populations Direct Dichotomous Eosinophil or Neutrophil Responses to Pulmonary Cryptococcus Infection

Many pulmonary infections elicit lymphocyte responses that lead to an accumulation of granulocytes in the lungs. A variety of lymphocytes are capable of directing eosinophils or neutrophils to the lungs, but the contribution of each subset remains enigmatic. In this study, we used a murine model to examine lymphocyte subsets that ultimately drive the eosinophil or neutrophil response to infection with the fungal pathogen Cryptococcus neoformans. We show that granulocytes are produced in the bone marrow, released into the blood stream, and accumulate in the lungs under the instruction of lung parenchymal lymphocytes. The eosinophils that populated the lungs of wild-type animals were highly dependent on Th cells or IL-5. Surprisingly, infected mice with Th cell impairment experienced a compensatory neutrophil response that required IL-17A. This unexpected swing in the response prompted us to investigate the ability of different lymphocyte subsets to produce this dichotomous eosinophilia or neutrophilia. We used mice with lymphocyte deficiencies to determine which of the remaining IL-5- or IL-17A- producing lymphocyte subsets dominated the neutrophil or eosinophil response. Finally, skewing the response toward neutrophil- inducing lymphocytes correlated with accelerated disease. Our data collectively demonstrate that the predominance of a lymphocyte subset determines the functional consequences of an immune response to pulmonary fungal infection that can ultimately affect disease. The Journal of Immunology, 2017, 198: 1627-1637.