The Role of T Helper (T_H)17 Cells as a Double-Edged Sword in the Interplay of Infection and Autoimmunity with a Focus on Xenobiotic-Induced Immunomodulation

Table 1

Mechanistic investigations on the role of T_H17 cells and their related molecules in various infectious diseases.

Diagnosis	Role	Observations on TH17-associated molecules	Citations
(1) Bacterial infections
Bacillus subtilis	Pathogenic/protective	Increased lung inflammation and collagen deposition; delay in bacterial clearance in IL-17R^−/− compared with WT counterparts	[118]
Francisella tularensis	Pathogenic	Intranasal inoculation induces TH17 response and PGE2 production in the lung; inhibition of PGE2 production increased IFN-γ and decreased bacteremia	[119]
Saccharopolyspora rectivirgula	Pathogenic	Induction of IL-17-mediated hypersensitivity pneumonitis in mice; reduced lung inflammation and fibrosis in IL-17R^−/− mice	[120, 121]
Klebsiella pneumoniae, Bordetella pertussis, & S. pneumoniae	Protective	Mounting of an IL-17 and IL-22 response; defects in TH17 response increased susceptibility	[12, 122]
Staphylococcus aureus	Protective	High infection incidence correlated with defect in TH17 response	[59]
Listeria  monocytogenes	Protective	IL-17-mediated cross-protection following immunization with M. pulmonis; blockade of bacterial growth following transfer of IL-17-producing γ δ and double negative α β T cells into RAG2^−/− mice	[30, 60]
Shigella flexneri	Protective	Restriction of bacterial growth mediated by TH17 response	[28]
Citrobacter and Salmonella sp.	Protective	Innate TH17 response-dependent protection; protective effect of IL-17 and IL-22; decrease in phagocytic activity and increase in bacterial burden upon IL-17 neutralization and its correlation with TH17 response in Hg-exposed mice	[29, 35, 38] and Hemdan and Abul El-Saad, unpublished
Mycobacterium tuberculosis and M. bovis	Protective	IL-17^−/− mice reveal a reduced IFN-γ production by CD4^+ T cells, impaired granuloma formation, and chemokine expression	[61]
Mycobacterium tuberculosis	Protective	Correlation of reduced TH17 responses in patients with active tuberculosis with decreased expression of IL-6R on CD4^+ T cells	[123]
Chlamydia sp.	Protective	Enhanced bacterial growth and decreased mouse survival upon applying anti-IL-17 mAb	[34]
	Pathogenic	Applying IL-17RA antagonist reversed the susceptible phenotype of C3H/HeN mice	[58]
Inflammatory bowel disease—IBD (Crohn's disease and ulcerative colitis)	Pathogenic	Enhanced differentiation TH17 and IL-17 expression levels and NK activities in IBD	[124, 125]
	Protective	IL-22 mediated protection against IBD	[54]
(2) Protozoal infection
Toxoplasma gondii	Pathogenic	IL-23-mediated IL-22 and MMP-2 upregulation in the ileum of infected mice; MMP-2 deficiency offered protection	[47]
	Protective	Increased mortality in IL-17^−/− mice	[126]
(3) Fungal infections
Candida sp.	Protective	Involvement of IL-17, IL-17F, IL-22, and IL-23 in mediating natural defense against candidiasis	[45]
Aspergillus fumigatus		Induced IL-17 response mediates pathogen clearance	[127]
(4) Viral infection
Theiler's murine encephalomyelitis virus infection	Pathogenic	Induction of antiapoptotic molecules by IL-17 and thereby promoting persistent infection; boosting lytic function of CTLs and ameliorating disease upon neutralizing IL-17; association of lower TH17 with higher virus-specific CD8^+ T cell responses in resistant mouse than in susceptible strain	[128]
Respiratory syncytial virus (RSV)	Pathogenic	Elevated IL-6 and IL-17 levels in tracheal aspirate samples from severely ill infants and in infected mice; IL-17 blockade decreased the exacerbated disease via increasing RSV-specific CD8^+ T cells, T-bet, IFN-𝛾, eomesodermin, and granzyme B	[129]
HBV	Pathogenic/protective	Distinct effects associated with heterogeneous TH17 populations: IL-17 with inflammation and ALT levels, IL-22 with protection of hepatocytes, and IL-21 with virus clearance	[130]
HCV	Pathogenic	Hepatitis-C-virus-infected patient revealed upregulated TH17 cell cytokines that became downregulated by combined treatment with pegylated IFN and ribavirin	[131]
Simian immunodeficiency virus (SIV)/HIV	Pathogenic	Induction of TGF-β and IL-18 during the acute phase in SIV-infected rhesus macaques proposed to be associated with induction of IL-17-producing NKT cells	[132]
	Protective	Association of disease progression with loss of TH17 and induction of TReg cells; TH17 cell frequency correlated negatively with viral load	[63, 133, 134]
Herpes simplex virus (HSV-1)		Infiltration of TH1 preceded TH17 cells, the latter showed lower responsiveness ability to HSV-1; diminished stromal keratitis severity in IL-17R^−/−-infected mice and upon IL-17 neutralization in WT mice	[135]
(5) Nematode infection
Trichinella spiralis	Pathogenic	Correlation of TH17 response with increase of smooth muscle contraction probably causing gut dysfunction; association of IL-17/IL-23 axis induction with increased mortality in mice coinfected with malaria and nematode	[136]