Th1 and Th2 patters of cytokine secretion correspond to activated effector phenotypes generated during an immune response. They do not exist among naive T cells. When first stimulated by antigen presenting cells (APCs), naive Cd4+ T cells principally or entirely produce IL-2, and then differentiate into phenotypes that secrete other cytokines. Thus Th1 and Th2 cells can both be derived form a single precursor cell.

Role of Innate Immune System  in driving Th1/Th2 development

Th1 and Th2 cells can develop in response to signals derived from the innate immune system. Activation of tissue macrophages, for example, through cell surface pattern receptors or by CD14 to which LPS has bound causes the secretion of IL-12 and TNF-alpha. IL-12 induces the differentiation of naive Th cells to the TH1 phenotype through its ability to maximize IFN-gamma and curtail IL-4 production by stimulated naive TH cells. 

Dendritic cells are also very important for driving TH cell development.  DCs recognize pathogens through receptors that sense common determinants found on pathogens. The best characterized of these receptors are the . After recognizing a pathogen, DCs migrate to the lymphoid organs, where they interact with T cells, transmitting information about the type of infection encountered and inducing a T-cell response. 

The production by  of either IL-4 or IL-12 in response to antigen stimulation is one of many key steps in the development of Th1 and Th2 cells. A Th1 response is initiated when dendritic cells are stimulated through their Toll-like receptors; this induces the secretion of IL-12, which signals undifferentiated (naive) CD4 T cells to differentiate into the Th1 lineage. Th2 responses are initiated when DCs encounter multicellular parasites or allergens. Neither the receptors that recognize these “type-2” antigens nor the dendritic-cell-associated molecules that induce Th2 responses are known. The key cytokine involved in Th2 differentiation is IL-4 which is produced by Th2 cells themselves. 

The cytokine environment in which antigen primed  differentiate determines the subset that develops. 

IFN-y,  , and IL-18 all are important for the TH1 subset.  leads to the phosphorylation of STAT4 and the subsequent activation of IFNy and  genes. The upregulation of these genes drives the development of TH1 cells.

IL-4 is essential for the development of a TH2 response. IL-4 leads to phosphorylation of STAT 6 and the subsequent activation of genes such as IL-4 receptor that promote TH2 development. In addition, in the relative absence of IL-12, IL-4 stimulation increases the Th2-dependent transcription factor GATA3 that further promotes Th2 differentiation. 

Role of T cell antigen receptor (TCR) stimulation by antigens

T cell antigen receptor (TCR) stimulation by antigens is also indispensable for both Th1 and Th2 cell differentation. For example, efficient TCR mediated activation of the p56lck, calcineurin, and Ras-ERK mitogen-activated protein kinase signaling cascase is required for Th2 cell generation.

Role o f Transcription Factors in Driving Th1/Th2 Development

Differential cytokine production by activated Th1 and Th2 cells is controlled at the level of gene transcription. At a gene level, two transcription factors, T-Bet and GATA-3 are key elements in determining subset commitment. The expression of T-Bet (which is upregulated in the presence of IFN-y) drives cells to differentiate into TH1 cells and suppresses their differentiation along the TH2 pathway. Expression of GATA-3 does the opposite. 

Drugs which may Drive Th1/Th2 Development 

Glucocorticoids: act on APCs to suppress the production of the main inducer of Th1 responses IL-12 in vitro and ex vivo. Because IL-12 is extremely potent in enhancing IFNy and inhibiting IL4 synthesis by T cells, the inhibition of IL-12 production may represent a major mechanisms by which glucocorticoids affect the Th1/Th2 balance.

Catecholamines (CAs): like norepineprhine (NE)/epinephrine drive a Th2 shift both at the level of APCs and Th1 cells.

Histamine: suppresses IL-12 and TNF-alpha and stimulates IL-10 production via H2 receptors. Histoamine is a well recongized mediator of acute inflammation and allergic reactions. These actions are mainly mediated by activation of H1 histamine receptors and include vasodilation, increased permeability of the vessel wall, edema, and in the lungs bronchoconstriction. Histamine, however, may also have important immunoregulatory functions via H2 receptors expressed on immune cells. Thus, histamine inhibts TNFalpha but potentiates IL-6 production. Because TNF-alpha is primarily a type 1 cytokine and IL-6 promotes B cell differentation, this suggest that histamine may promote humoral immunity.

Glutathione (GSH): Studies report that inracellular glutathione levels in APC influence the Th1/Th2 cytokine resposne pattern. GSH depletion reportedly inhibits Th1 associated cytokine production an/or favors Th2 associated responses. It has even been suggested that classical response pattern differences to cahllenge with parasitic organisms that have led to the characterization of mouse strains as “Th2” or “Th1” may simply relfect a differential sensitivity to GSH depletion.