Candida albicans infection enhances immunosuppression induced by cyclophosphamide by selective priming of suppressive myeloid progenitors for NO production.
Systemic infections caused by fungi after cytoreductive therapies are especially difficult to deal with in spite of currently available antimicrobials. However, little is known about the effects of fungi on the immune system of immunosuppressed hosts. We have addressed this by studying the in vitro T cell responses after systemic infection with Candida albicans in cyclophosphamide-treated mice. After cyclophosphamide treatment, a massive splenic colonization of the spleens, but not lymph nodes, by immature myeloid progenitor (Ly-6G(+)CD11b(+))cells is observed. These cells are able to suppress proliferation of T lymphocytes via a nitric oxide (NO)-dependent mechanism. Systemic infection with a sublethal dose of C. albicans did not cause immunosuppression per se but strongly increased NO-dependent suppression in cyclophosphamide-treated mice, by selective priming of suppressive myeloid progenitors (Ly-6G(+)CD11b(+)CD31(+)CD40(+)WGA(+)CD117(low/-)CD34(low/-)) for iNOS protein expression. The results indicate that systemic C. albicans infection can augment the effects of immunosuppressive therapies by promoting functional changes in immunosuppressive cells.
Angulo
Iñigo
I
Centro de Biología Molecular, Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Jiménez-Díaz
María Belén
MB
García-Bustos
José Francisco
JF
Gargallo
Domingo
D
de las Heras
Federico Gómez
FG
Muñoz-Fernández
María Angeles
MA
Fresno
Manuel
M
D000818:Animals; D002177:Candidiasis / Q000276:immunology*; D003520:Cyclophosphamide / Q000633:toxicity*; D004790:Enzyme Induction; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D003520:Cyclophosphamide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse