In response to an infection, a variety of cells of the innate and adaptive immune systems become activated and collaborate in the effort to control and eliminate invading pathogens. CD4 T cells (also known as Th cells) play critical roles during adaptive immune responses [1
]. They help B cells to produce antibody and to undergo class switching and affinity maturation; they recruit and activate CD8 T cells, macrophages, neutrophils, eosinophils, basophils and other effector cells. They also directly act on many tissue cells, including epithelial cells and mucosal cells, during the process of pathogen clearance. The diverse functions of CD4 T cells are determined by their cytokine secretion patterns and their tissue locations.
Beginning in the 1980s, immunologists came to believe that different types of Th cells were involved in humoral and cell-mediated immune responses. In 1986, Coffman and Mosmann showed the existence of Th1 and Th2 clones differing from each other in the cytokines they produced [2
]. Th1 cells mainly produce IFNγ, which is important for macrophage activation and clearance of intracellular pathogens, whereas Th2 cells produce IL-4, IL-5, IL-10 and IL-13, later shown to be critical for IgE production, eosinophil recruitment and clearance of extracellular parasites [3
]. Th1 and Th2 cells are also involved in many diseases. Th1 cells were thought to cause many organ-specific autoimmune diseases, whereas Th2 cells are responsible for asthma and other allergic reactions.
With the discovery of IL-23, which shares the subunit p40 with IL-12, it became clear that many autoimmune diseases, earlier attributed to Th1 cells, are indeed induced by other Th cells that are IL-23 responsive [5
]. Soon, this lineage of Th cells was identified as Th17 cells, which produce many cytokines including IL-17a, IL-17f, IL-22 and IL-21 [6
]. In addition to their involvement in autoimmune diseases, Th17 cells also play critical roles during immune responses against extracellular bacteria and fungi [8
Naturally occurring regulatory T cells (nTregs) develop in the thymus [9
]. IL-2 and TGFβ signaling, as well as CD28 co-stimulation and self-recognition seem to be important for nTreg generation. At essentially the same time that Th17 cells were discovered, it was shown that treatment of naïve peripheral CD4 T cells with a TCR stimulant and with TGFβ plus IL-2 caused the appearance of inducible regulatory T cells (iTregs) [10
]. The Treg population found in vivo
consists of both nTregs and iTregs, both of which express transcription factor Foxp3. Like nTregs, iTregs may also be involved in self-tolerance, immune modulation and promoting immune responses under certain circumstances [11
Thus far, four CD4 Th cell lineages are generally recognized, namely, Th1, Th2, Th17 and Treg cells [1
]. The cytokine environment during priming and the consequent activation of specific transcription factors are two key elements controlling Th cell differentiation from naïve CD4 T cells. A distinct set of cytokines promotes the differentiation processes for each lineage: IL-12/IFNγ for Th1; IL-4/(IL-2, IL-7, TSLP) for Th2; TGFβ/(IL-6, IL-21, IL-23) for Th17 and TGFβ/IL-2 for Tregs. The transcription factors that govern the differentiation of these cells are also well defined: T-bet/Stat4 for Th1, GATA3/ Stat5 for Th2, RORγt/Stat3 for Th17 and Foxp3/Stat5 for Tregs.
Other potential Th cell ‘lineages’ have been proposed including Th3 cells [12
] (TGFβ-producing CD4 T cells), Tr1 cells [14
] (IL-10-producing CD4 T cells), Th9 cells [15
] (IL-9-producing CD4 T cells) and Tfh cells [17
] (T follicular helper (Tfh) cells located in the follicular regions of lymph nodes and spleen). Since the ‘signature’ cytokines produced by these Th cells are also the products of Th1/Th2/Th17/Treg cells and the transcription factors they express are not unique, whether these cells represent lineages separate from the known four lineages is uncertain and needs further investigation. The relationships between Th1/Th2/Th17/Treg and Th3, Tr1, Th9, Tfh cells are shown in .
Figure 1 T helper lineages and subsets. CD4 T helper cells can be divided into at least four lineages, namely, Th1, Th2, Th17 and Treg. These cells express master transcription factors (shown inside the cells, pSTATs stands for phosphorylated active STATs) and (more ...)