Table 1.

Summary of animal studies to elucidate the role of PRRs in the development of T1D

PRR	Mouse Strain	Spontaneous Disease or Administered Treatment	Outcome	Mechanisms	References
TLR
TLR2	TLR2-/-B6 TLR2-/-NOD	STZ-induction or spontaneous	Protection	Apoptotic β-cell injury could stimulate the priming of diabetogenic T cells through a TLR2-dependent activation of antigen-presenting cells	[33]
	TLR2-/-NOD	Spontaneous	Higher incidence of diabetes and more severe insulitis in GF mice than SPF mice	Commensal microbes may regulate the pro-diabetic effect	[35]
	NOD	Treated prediabetic mice with agonist Pam3CSK	Protection	Increased number and function of CD4+CD25+ Tregs, also endowing dendritic cells with tolerogenic properties	[37]
	NOD	Zymosan and β-cell Ag at prediabetic or early hyperglycemic stages	Protection	Promoted Foxp3+ Tregs and IL-10, IL-4 and Il-17 expressing CD4+T cells	[41]
TLR3	NOD or BB rats	Administration of low-dose poly (I:C)	Protection	Possible recruitment of regulatory cells or induction of suppressor cell activity.	[47,49]
	BBDR rats	Administration of high-dose poly (I:C)	Induction of diabetes	Induced the expansion of peripheral blood NK cells	[48]
	TLR3-/-NOD	Spontaneous	No effect		[65]
	RIP-GP mice (mixed background of 129Sv × C57BL/6)	Immunized with gp33 and adoptively transferred with 107 splenocytes derived from LCMV-gp33/H-2Db-specific TCR-transgenic 318 mice. Then treated with 200 μg of poly(I:C).	Diabetes induction	MHC I up-regulated in beta cells.	[66]
	TLR3-/- NOD	CVB4 inoculation	Protection	Islets less infiltrated with T cells compared to WT	[67]
TLR4	NOD	TLR4/MD-2 antibody	Reverse new-onset diabetes	Induced APC tolerance and expansion of Tregs.	[72]
	TLR4-/-NOD	Spontaneous	Acceleration	Reduced capacity of Tregs to inhibit T cell proliferation. Alteration of gut microbiota.	[12,35,75]
	NOD/scid	Co-transfer of LPS-activated B cells with diabetogenic splenocytes	Protection	Down-regulated Th1 autoimmunity and more secreted TGFp to inhibit APC activity	[76]
TLR5	TLR5-/-NOD	Spontaneous	No effect		Unpublished data
TLR7	NOD or NY8.3NOD	Administration of TLR7 agonist with or without anti-CD40	Acceleration	Activated lymphocytes and promoted the production of pro-inflammatory cytokines	[68]
	RIP-GP mice (mixed background of 129Sv × C57BL/6)	Immunized with gp33 and adoptively transferred with 107 splenocytes derived from LCMV-gp33/H-2Db-specific TCR-transgenic 318 mice, followed by administration of R-848.	Diabetic induction	Enhanced production of IFN-α and upregulation of pancreatic MHC II.	[66]
	TLR7-/-NOD	Spontaneous	Protection		Unpublished data
TLR9	TLR9-/-NOD	Spontaneous	Protection	Upregulated CD73 in immune cells accompanying with lower levels of pro-inflammatory cytokines and higher levels of anti-inflammatory cytokines in CD4+ T cells.	[65,87]
	TLR9-/-NOD	Spontaneous	Protection	Reduced levels of IFNα in PLNs and reduced frequencies of diabetogenic CD8+ T cells	[88]
MyD88	MyD88-/-NOD	Spontaneous	Complete protection in SPF	Altered gut microbiota	[12]
TRIF	TRIF-/-NOD	Spontaneous	No significant effect		Unpublished data
	TRIF-/-MyD88-/-NOD	Spontaneous	Reversed protection from diabetes in SPF conditions.		[35]
NLR
NOD2	NOD2-/-NOD	Spontaneous	Protection	Altered gut microbiota	Unpublished data
NLRP3	NLRP3-/-NOD	Spontaneous	Protection	Altered T cell activation, Th1 differentiation and pathogenic T cell migration to the pancreatic islet.	[113]