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T Cell-Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity during Cryptococcus neoformans Infection.


ABSTRACT: Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen but the cell signaling pathways that drive T cell responses regulating antifungal immunity are incompletely understood. Notch is a key signaling pathway regulating T cell development, and differentiation and functional responses of mature T cells in the periphery. The targeting of Notch signaling within T cells has been proposed as a potential treatment for alloimmune and autoimmune disorders, but it is unknown whether disturbances to T cell immunity may render these patients vulnerable to fungal infections. To elucidate the role of Notch signaling during fungal infections, we infected mice expressing the pan-Notch inhibitor dominant negative mastermind-like within mature T cells with C. neoformans Inhibition of T cell-restricted Notch signaling increased fungal burdens in the lungs and CNS, diminished pulmonary leukocyte recruitment, and simultaneously impaired Th1 and Th2 responses. Pulmonary leukocyte cultures from T cell Notch-deprived mice produced less IFN-?, IL-5, and IL-13 than wild-type cells. This correlated with lower frequencies of IFN-?-, IL-5-, and IL-13-producing CD4+ T cells, reduced expression of Th1 and Th2 associated transcription factors, Tbet and GATA3, and reduced production of IFN-? by CD8+ T cells. In contrast, Th17 responses were largely unaffected by Notch signaling. The changes in T cell responses corresponded with impaired macrophage activation and reduced leukocyte accumulation, leading to diminished fungal control. These results identify Notch signaling as a previously unappreciated regulator of Th1 and Th2 immunity and an important element of antifungal defenses against cryptococcal infection and CNS dissemination.

SUBMITTER: Neal LM 

PROVIDER: S-EPMC5513675 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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T Cell-Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity during <i>Cryptococcus neoformans</i> Infection.

Neal Lori M LM   Qiu Yafeng Y   Chung Jooho J   Xing Enze E   Cho Woosung W   Malachowski Antoni N AN   Sandy-Sloat Ashley R AR   Osterholzer John J JJ   Maillard Ivan I   Olszewski Michal A MA  

Journal of immunology (Baltimore, Md. : 1950) 20170614 2


<i>Cryptococcus neoformans</i> is a ubiquitous, opportunistic fungal pathogen but the cell signaling pathways that drive T cell responses regulating antifungal immunity are incompletely understood. Notch is a key signaling pathway regulating T cell development, and differentiation and functional responses of mature T cells in the periphery. The targeting of Notch signaling within T cells has been proposed as a potential treatment for alloimmune and autoimmune disorders, but it is unknown whether  ...[more]

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