Table 1.
disease model | in vivo, loss-of-function strategy | outcome | citation | |
---|---|---|---|---|
host defence | Trypanosoma cruzi infection | deletion of Notch2 in CD4+ T cells | impaired survival; impaired GZMB expression | [45] |
mycobacteria-elicited pulmonary granulomatosis | systemic anti-Dll4 treatment | larger granulomas; decreased Th17 cytokines (IL-17/17A/F, -6, -21) | [46] | |
Leishmania major infection | deletion of Notch1 and Notch2 in T cells | susceptibility to infection, impaired IFNγ | [47] | |
Influenza infection | deletion of Notch1 and Notch2 in CD8+ T cells; systemic anti-Dll1 treatment; GSI treatment | impaired viral clearance; decreased terminal effector cell differentiation, impaired IFNγ; impaired survival | [48,49] | |
Listeria monocytogenes infection | deletion of Notch1 and Notch2 in CD8+ T cells | decreased short-term effector cell differentiation, impaired IFNγ | [50] | |
Cryptococcus neoformans infection | DNMAML expression in T cells | increased fungal burden, impaired Th1/Th2 response | [51] | |
autoimmunity | experimental autoimmune encephalomyelitis (multiple sclerosis) | GSI treatment; systemic anti-Dll4 treatment; systemic anti-Notch3 treatment; DNMAML expression in T cells | decreased disease scores, impaired IFNγ; impaired IL-17A/IFNγ in CNS | [52–57] |
alloimmunity | graft-versus-host disease | DNMAML expression in donor T cells; deletion of Notch1 and Notch2 or Rbpj in donor T cells; systemic anti-Notch1/2 or anti-Dll1/4 treatment; deletion of Dll1/4 in recipient CCL19+ stromal cells |
decreased GVHD severity scores, increased survival, impaired IFNγ, increased Treg expansion | [58–66] |
heart transplant | systemic anti-Dll1 treatment + CTLA4-Ig/CD28KO; systemic anti-Dll1/4 treatment; DNMAML expression in T cells; systemic anti-Notch1 ± CTLA4-Ig treatment; Deletion of Notch1 in Tregs | delayed cardiac allograft rejection, impaired GZMB; impaired IFNγ/IL-4, decreased graft infiltration, decreased donor-specific alloantibodies | [67–69] | |
lung transplant | systemic anti-Notch1 + anti-CLTA4-Ig treatment | preserved airway patency with less lymphocytic infiltrations and delayed lung allograft rejection | [69] | |
human skin graft to mouse with chimeric human haematopoietic system | systemic anti-Notch1 | decreased T cell infiltration, greater proportion of Tregs infiltrating, improved vascularity | [69] | |
model antigens | H-Y antigen | deletion of Dll4 in DCs | impaired CD4+ T cell activation and IL-2 production | [70] |
keyhole limpet Haemocyanin alum, Schistosoma mansoni egg extract | deletion of Notch1 and Notch2 or Rbpj in T cells | impaired CD4+ T cell activation | [71] |