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T Cell-Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity
during Cryptococcus neoformans Infection
#MMPMID28615417
Neal LM
; Qiu Y
; Chung J
; Xing E
; Cho W
; Malachowski AN
; Sandy-Sloat AR
; Osterholzer JJ
; Maillard I
; Olszewski MA
J Immunol
2017[Jul]; 199
(2
): 643-655
PMID28615417
show ga
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.
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