**2. Th17 cells**

Faced with any antigenic stimulus, either an intracellular or extracellular pathogen or any tissue homeostatic alteration, naïve CD4+ T-cells respond via activation, proliferation, and finally differentiation into specialized T-effector cell subsets which are specifically programmed to deal with the offending agent/s. One such specialized T-effector cell subset is comprised of Th17 cells, best known as a host-defensive effector T-cell subset at barrier mucosal tissues (intestine, lung, skin) with a prime role in providing immunity against fungi and other extracellular pathogens and in sustaining gut barrier integrity by transdifferentiating into Th1-like or Treg-like cells [5]. Retinoic acid-related orphan receptor-gamma (RORγt), a signature ligand-dependent transcription factor for Th17 cells has been characterized as the molecular orchestrator of Th17 cell program. RORγt belongs to a subfamily of nuclear receptors, encoded by the master switch gene *RORA-C* (or *NR1F1-3*) [6]. A variety of transcriptional regulators of RORγt, as well as other transcription factors that either interact with RORγt or bind the promoter or the intergenic regions of the *IL-17* gene locus, play a crucial role in the generation of Th17 cells (**Figure 1**) [7].

Th17 cells exhibit much superior plasticity compared to other T-cell subsets and epitomize a highly functionally diverse effector T cell population and also display stem cell-associated features [8]. Transforming growth factor (TGF)-β1 and IL-6 induced non-pathogenic/anti-inflammatory Th17 cells have been shown to play an important role in supporting cellular and organismal metabolic homeostasis as well [9]. However, Th17 cells are also recognized for their pathogenicity against the host, due to their association with several autoimmune diseases including psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and diabetes mellitus. TGF-β3-induced, IL-23- dependent, functionally distinct pathogenic Th17 cells are characterized by different molecular, biochemical, and metabolic profiles (**Table 1**), conferring a proinflammatory phenotype to this effector T-cell subset [10].

Th17 cell evolution towards pro-inflammatory *vs*. anti-inflammatory or homeostatic phenotype is determined not only by a set of specific polarizing cytokines (TGF-β3 + IL-23 or IL-1β + IL-6 + IL-23 *vs.* TGF-β1 + IL-6) but also by a dynamically changing metabolic milieu comprised by a variety of metabolites *viz*. fatty acids, phospholipids, cholesterol intermediates, oxysterols and amino acids [11–16]. These metabolites drive Th17 plasticity by changing the latter's epigenetic landscape by serving as substrates for chromatin-modifying enzymes [17]. This remarkable metabolic heterogeneity can hugely influenceTh17 cell lineage plasticity and their effector function, thereby impacting the course of Th17-associated autoimmune inflammatory diseases, including psoriasis [18].

*Th17/IL-17, Immunometabolism and Psoriatic Disease: A Pathological Trifecta DOI: http://dx.doi.org/10.5772/intechopen.102633*

#### **Figure 1.**

*IL-17 induced "Psoriasogenicity": psoriatic march. (A) A constellation of regulatory factors including hypoxiainducible factor (HIF)-1α (with recruited factor p300 having histone acetyltransferase activity), runt-related transcription factor (RUNX1), basic leucine zipper ATF-like transcription factor (BATF)- Jun B heterodimer, nuclear factor of activated T cells (NFAT), p65 NF-kB subunit, and signal transducer and activator of transcription (STAT) 3 act as co-operators of RORC gene, enhancing its expression and resulting in increased Th17- lineage-specific transcription factor RORγt. (B) RORγt binds to ROR response elements (RORE) located in CNS2 (conserved non-coding sequences) of the IL-17 gene, and globally controls its transcription. The effect of transcriptional regulator RUNX1 (binding to CNS2 region of IL-17) is also dependent on RORγt; HIF-1α (coactivator for RORγt) physically associates with RORγt promoting IL-17 expression without direct binding on IL-17 locus. Nuclear protein inhibitor of kB (IκB)ζ, is another regulator, that also binds CNS2 elements in the IL-17 locus. Various other transcription regulators that promote IL-17 gene expression by binding to its promoter include BATF, JunB, interferon regulatory factor (IRF)4, STAT3, Kruppel-like factor (KLF) 4. (C) IL-17 leads to induction of various genes encoding for inflammatory mediators, chemokines, antimicrobial peptides, and the osteoclastogenic factor RANKL. This leads to the wide-spread biological effects of IL-17, affecting a variety of cell types/tissues including keratinocytes, endothelial cells, fibroblasts, epithelial cells, and bone.*


*Ahr, aryl hydrocarbon receptor; c-maf, c-musculoaponeurotic fibrosarcoma expression; csf2, colony stimulating factor; T-bet, T-box expressed in T cells; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; MUFA, monounsaturated fatty caids; α-KG, alpha-ketoglutarate; 2-HG, 2-hydroxyglutarate.*

### **Table 1.**

*Differences between non-pathogenic and pathogenic Th17 cells.*
