**4. T helper subtype 9 (Th9) cells**

Certain inflammatory conditions give rise to the T helper subtype 9 (Th9) cells of unknown functional contribution to the immune response [40, 41]. The in vitro development of effector cells specific to constituents of oligodendrocytes (myelin oligodendrocyte glycoprotein) Th17, Th1, Th2, and Th9 allowed evaluating the encephalitogenic activity in adoptive transfer. All Th1, Th17, and Th9 subpopulations but not Th2 successfully induced experimental allergic encephalitis [23]. The Th9 cells might express varied chemokine patterns involved in different immune responses. Their effector function balanced by regulatory T cells induces regulatory activity restoring homeostasis. This recently described Th9 subset of helper lymphocytes may escalate chronic inflammation under certain conditions independently from Th1, Th2, Th17, and regulatory T cells [42].

#### **5. T helper subtype 22 cells**

Another LT helper subpopulation, the Th22, has been recently identified in epidermic infiltrates in a variety of inflammatory skin disorders, including psoriasis [43]. They secrete IL22 and TNFα but not IFNg, IL4, or IL17, and their clones derived from psoriatic patients are stable in culture, exhibiting a distinctive transcription profile compared with the already mentioned subpopulations. Secretion profile includes fibroblast growth factors and chemokines potentially involved in angiogenesis and fibrosis [44].

## **6. T helper subtype 17 cells**

Differentiation of Th17 cells, like Th1 and Th2 cells, requires the co-participation of CD28 and ICOS after the initial stimulus derived from antigenic recognition via

**41**

*Immune-Mediated Inflammation: Human T CD4 Helper Lymphocyte Diversity and Plasticity…*

the TCR complex (TCR, CD3, ζ chains) for differentiation from virgin CD4+ T cells [45]. Ivanov and colleagues suggested that the nuclear receptor ROR gamma T is the key transcriptional factor [46] in the differentiation of the Th17 lineage. The Th17

Differentiation to Th17 requires IL6, TGFβ, and IL23 [48], whereas IL1 and TNFα might be involved in Th17 maturation. According to this model, IL27, another

The proinflammatory cytokine IL-17, originally named IL-17A, has been the subject of intense research since its discovery in 1993 [52]. Interest in this cytokine increased considerably when its production by a specific subset of CD4 + T cells, the so-called Th17 cells [53], was reported. Nevertheless, Th17 lymphocytes can change their phenotype to Th1 or Th2 cells depending on the dominant cytokines [2, 54]. **Figure 2** illustrates how this plasticity can influence arthritis and cardiovascular risk. Other immune cells subsets can also synthesize and express IL-17, including CD8 + T cells (CD8 + IL17 T-cell, or Tc17). Differentiation of CD8 (+) T cells depend on the antigen, co-stimulatory molecules, cytokines, and transcription factors

Since Th17 hyperactivation is responsible for the Th17/Treg imbalance in certain pathologies, IL-17A might be considered a potential therapeutic target in modulating

Following Th3 cell identification and characterization based on their functions in the intestinal mucosa, many studies investigated the phenotypic characteristics of conventional Treg cells in different tissues and pathological situations. The Th3 cells (CD4+ TGFβ +) and the Foxp3+ can be induced by oral tolerance, and the TGFβ released by iTreg prevents experimental colitis [57]. Though regarded as separate lineages, the induced Treg (iTreg) and Th3 cells are substantially superimposed. Regulatory T cells and maintenance of self-tolerance rely on natural Treg cells,

typically expressing CD4, CD25, and Foxp3. They develop in the thymus and

The Treg-induced cells (iTreg), another subset of Treg cells, are also generated in the periphery during an active immune response. In fact, CD4 + CD25− cells in the periphery can be converted, in the presence of TGFβ and IL10 into CD25 + CD4 + Foxp3 + cells. The iTreg cells induced by IL-10 are called Tr1 cells and if induced by TGFβ are called Th3. One subpopulation of nTreg expresses activation markers suggesting that it comprises autoreactive Tregs continuously

Three suppression mechanisms, not fully elucidated, have been proposed to explain the inhibitory actions of Treg cells on activated T cells. These are the contact-dependent inhibition between Treg and effector cells, the consumption and limitation of growth factors like IL-2, and the inhibition of LT effectors by the production of soluble inhibitory cytokines (TGFβ, IL-10, and IL-35) and CTL4

ligands of the Treg which interacts with the CPA molecules [59].

member of the IL12 family, programs the TCD4+ cells to differentiate to Th1 inducing the expression of IL12Rβ2. The IL12 is required for the differentiation of the programmed cells into Th1 cells producing IFNγ. In turn, IL23, a member of the IL12 family [49], triggers the proliferation of Th1 cells from memory cells and induces the development of inflammatory Th17 cells [50]. Conversely, IL27 inhibits differentiation to Th17 cells by an unknown mechanism suppressing inflammation. The relative amount of IL6 and TGFβ in the cellular microenvironment is crucial to

*DOI: http://dx.doi.org/10.5772/intechopen.89230*

the severity of inflammation [51].

**7. Regulatory T cells**

recognize specific autoantigens [58].

activated by tissue autoantigens.

cells producing IL17 induce inflammatory responses [47].

inducing them to progress to Tc1, Tc2, Tc9, Tc17, or TCD8 [55].

Th1 activity enhancing the regulatory response [56].

*Immune-Mediated Inflammation: Human T CD4 Helper Lymphocyte Diversity and Plasticity… DOI: http://dx.doi.org/10.5772/intechopen.89230*

the TCR complex (TCR, CD3, ζ chains) for differentiation from virgin CD4+ T cells [45]. Ivanov and colleagues suggested that the nuclear receptor ROR gamma T is the key transcriptional factor [46] in the differentiation of the Th17 lineage. The Th17 cells producing IL17 induce inflammatory responses [47].

Differentiation to Th17 requires IL6, TGFβ, and IL23 [48], whereas IL1 and TNFα might be involved in Th17 maturation. According to this model, IL27, another member of the IL12 family, programs the TCD4+ cells to differentiate to Th1 inducing the expression of IL12Rβ2. The IL12 is required for the differentiation of the programmed cells into Th1 cells producing IFNγ. In turn, IL23, a member of the IL12 family [49], triggers the proliferation of Th1 cells from memory cells and induces the development of inflammatory Th17 cells [50]. Conversely, IL27 inhibits differentiation to Th17 cells by an unknown mechanism suppressing inflammation. The relative amount of IL6 and TGFβ in the cellular microenvironment is crucial to the severity of inflammation [51].

The proinflammatory cytokine IL-17, originally named IL-17A, has been the subject of intense research since its discovery in 1993 [52]. Interest in this cytokine increased considerably when its production by a specific subset of CD4 + T cells, the so-called Th17 cells [53], was reported. Nevertheless, Th17 lymphocytes can change their phenotype to Th1 or Th2 cells depending on the dominant cytokines [2, 54]. **Figure 2** illustrates how this plasticity can influence arthritis and cardiovascular risk.

Other immune cells subsets can also synthesize and express IL-17, including CD8 + T cells (CD8 + IL17 T-cell, or Tc17). Differentiation of CD8 (+) T cells depend on the antigen, co-stimulatory molecules, cytokines, and transcription factors inducing them to progress to Tc1, Tc2, Tc9, Tc17, or TCD8 [55].

Since Th17 hyperactivation is responsible for the Th17/Treg imbalance in certain pathologies, IL-17A might be considered a potential therapeutic target in modulating Th1 activity enhancing the regulatory response [56].
