**7. Regulatory T cells**

*Cells of the Immune System*

with them [39].

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

**5. T helper subtype 22 cells**

**6. T helper subtype 17 cells**

dently from Th1, Th2, Th17, and regulatory T cells [42].

Curiously, ThF cells dysfunction may induce systemic autoimmunity. The ThF cells comprise a TCD4+ subpopulation restricted to the B areas of the lymphatic organs, critically involved in the events following the interaction of dendritic cells with the virgin T lymphocytes in the secondary lymphatic organ T zone [35]. The development of follicular homing capacity by activated T cell helper is the first event in the generation of ThF cells. Virgin T cells expressing CD62L and CCR7 enter the secondary lymphatic organs in the T paracortical lymphoid region, and T-lymphocyte activation induces sub-sensitivity to lymphoid chemokines along with an increase in follicular chemokines CXCL13 (also known as B cell-attracting

Activated ThF and lymphoblast B lymphocytes express the CXCR5 receptor, which confers follicle-positive tropism, and the stroma and dendritic follicular cells express the ligand CXCL13. Follicular dendritic cells supply proliferative, antiapoptotic signals, and ThF lymphocytes undergo changes increasing antigenic specificity and promote the differentiation of lymphoblasts into plasma cells or B lymphocytes with memory. The antigen-dependent T-B interaction is critical in triggering the humoral immune response [37]. The T-B collaboration is essential to generating short-lived plasma cells and inducing the germinal center where they trigger isotype change and somatic hypermutation, yielding high-affinity long-lived plasma cells and memory cells [38]. Regarding ThF relationship with Th1, Th2, and Th17 subpopulations, some authors mention that ThF cells produce IL4, IFNγ, and IL17, respectively, associated

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 indepen-

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].

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

chemokine BCA-1 or B lymphocyte chemoattractant BLC) [36].

**40**

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 recognize specific autoantigens [58].

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 activated by tissue autoantigens.

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].

**Figure 3.**

*Modulation of T lymphocyte function by TGFβ factor and its importance in Th1-mediated diseases. TGFb released by different types of regulatory cells modulates the inflammatory activity of all effector cells, Th1 cells included.*

The T-regulatory activity (Treg) is pathologically low in both psoriasis and atherosclerosis [60]. The activity of pathogenic T cells is regulated by Treg cells activity via IL-10 and TGFβ [61]. The TGFβ inhibits Th1, and Th2 differentiation favors Th1 and Th17 hyperactivity [62] in both pathologies [60]. The increase in TGFβ [63] was reported inversely correlated with cardiovascular and psoriatic severity.

The critical role of TGFβ and Treg cells was evidenced by the finding that TGFβdeficient mice developed multiple inflammatory diseases [64–66].

Both nTreg cells and Tr1-induced cells are able to produce IL10. The relevance of IL10 was evidenced by the specific blocking experiments of lymphocyte IL-10 triggering protection against inflammatory processes. The Tr1 cells expressing IL-10 require the presence of TGFα [67]. Regarding Th2-mediated counterregulation, the Th2 produces anti-inflammatory IL-4, IL-5, and IL-13 which decrease Th1 cells activity. The proinflammatory, metabolic, and systemic mechanisms that operate in the pathogenesis of psoriatic disease may explain the accelerated atherosclerotic process in these patients (**Figure 3**). Serum level of proinflammatory cytokines can increase cell-mediated immunity, which upon decreased regulatory Th2 activity and Treg level promote endothelial infiltration of inflammatory cells and plaque formation [68].

### **8. Conclusions**

The heterogeneity of the T cells in general and TCD4 helper, in particular, may reflect divergent pathways in response to epigenetic factors or different stages of a unique differentiation pathway. Adhesion molecules, e.g., LFA1 and ICAM, CCR and CXCR chemokine receptors, and activation molecules, among others of undetermined function, reflect the transition.

The heterogeneity may obey to a programmed developmental process or to microenvironmental stimulation. Immunosuppressive or stimulatory signals like cytokines seem crucially involved though both may participate. This information is expected to shed light on the possible pathogenic role of Th cells in human inflammatory diseases beyond the Th1/Th2 paradigm.

The relationships between the classic Th1/ Th2 and the more recently defined Th17/iTreg/ Tfh/Th9 cells and effector-regulatory cell interactions need clarification regarding their pathogenic role in human inflammatory diseases.

**43**

**Author details**

Sabrina Porta2

Francisco Capani1,3

Rodolfo Alberto Kölliker Frers1,2, Matilde Otero-Losada1

Council, ININCA, UBA-CONICET, Buenos Aires, Argentina

3 Pontifical Catholic University of Argentina, Buenos Aires, Argentina

, Eduardo Kerzberg2

1 Institute of Cardiological Research, University of Buenos Aires, National Research

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Vanesa Cosentino2

2 Hospital Ramos Mejía, Buenos Aires, Argentina

provided the original work is properly cited.

\*Address all correspondence to: molly1063@gmail.com

\*, María Inés Herrera1,3,

and

, Lucas Udovin1

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

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

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