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The initial step in the polarization of naive T cells is the interaction of APCs, mostly DCs, with a non-self or “danger signaling” antigen. The physical nature of the antigen and the cytokines subsequently released by the APC encountering this antigen determines whether a Th1 or Th2 skewed immune response occurs. For example, when APCs are challenged with intracellular pathogens, like viruses, a common cytokine secreted is IL-12. This cytokine promotes the differentiation of naive T cells into Th1 cells. Maturing Th1 cells then produce the cytokine IFN-γ, which feeds back in an autocrine loop to trigger the development of more APCs as well as further promote the maturation of naïve T cells into Th1 cells. Additional cytokines, like IL-18, also can be secreted to further influence Th1 development by enhancing IL-12 dependent Th1 cell differentiation and effector function. This self-perpetuating cycle of Th1 dominant cytokines persists until the immune challenge is sufficiently reduced.
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If APCs are challenged with blood-borne pathogens, cytokines like IL-4 are released to promote Th2 cell differentiation. Additional cytokines like IL-13 also are secreted under certain conditions, and further promote Th2 polarization and development in an IL-4 independent manner. Maturing Th2 cells continue to release IL-4, generating an autocrine feedback loop that further increases the differentiation of naïve T cells to Th2 cells. Th2 cell dominant cytokines are continuously secreted until the blood-borne pathogens are removed or sufficiently reduced. When naïve T cells become Th1 or Th2 polarized they are committed to that specific pathway and cannot be reversed. Cytokines secreted by Th2 cells activate specific B cells for antigen clearance as well as for antibody class switching. Cytokines secreted by the Th1 cells primarily promote inflammation and the activation of cytotoxic T cells. These Th1 and Th2 specific cytokines interact with each other to antagonize their respective maturation and actions. For example, Th1 cells secrete IFN-γ which inhibits proliferation of Th2 cells, whereas Th2 cells secrete the cytokine IL-4 that prevents Th1 cell differentiation. Further regulation of Th1 and Th2 cells occurs with additional subsets of T cells, termed regulatory T cells (Treg) or Th3 cells. Specific regulation of T cells by Th1, Th2 or Treg/Th3 cells will be discussed in the next sections.

Th1 Subset

The Th1 cell pathway supports cell-mediated immunity, preventing disease from intracellular pathogens like viruses, certain bacteria, yeast, fungi and protozoans. Th1 cellassociated immunity also has a major role in preventing tumor cell development. However, if naïve T cells are chronically Th1 polarized, an overactive cell-mediated immune response can result. For example, persistently high secretion of IL-12 will cause Th1 cells to produce large amounts of pro-inflammatory cytokines like IFN-γ and TNF-α. These cytokines further activate macrophages to produce additional pro-inflammatory mediators (i.e. IL- 12 and IL-18) in a positive feedback loop that has potential pathological consequences (see figure 1).

Persistent Th1-mediated inflammation of the gastrointestinal tract is associated with pathologies like Crohn’s disease,3 H. pylori gastritis, cellular autoimmunity, chronic recurrent inflammation and possibly rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. This Th1 rigidity and the potential pathological consequences can be moderated by upregulating the production of Th2 dominant cytokines, like IL- 4, IL-10 and IL-13. These cytokines inhibit the development of Th1 cells and macrophage activation and, therefore, can prevent inflammatory tissue damage resulting from an overabundance of Th1 cell stimulation. Furthermore, the immunosuppressive cytokines IL-10 and TGF-β, released by regulatory T cells, also down-regulate Th1 rigidity and help control colitis and other inflammatory diseases. Certain probiotic strains can help down-regulate these Th1 dominant disorders and return balance to the immune response. For example, TNF-α plays a key role in the pathogenesis of intestinal inflammation in Crohn’s disease, a disease associated with Th1 polarization. Borruel et al. (2002) studied the effect of probiotic bacteria on TNF-α production by obtaining ileal specimens from ten patients with Crohn’s disease. They observed a significant reduction in the production of TNF-α by inflamed Crohn’s disease mucosa when cultured with L. casei or L. bulgaricus, but not with L. crispatus or E. coli. The authors concluded that these probiotic strains had the ability to attenuate the release of the pro-inflammatory cytokines that promote Th1 rigidity by interacting with the intestinal mucosal immunocompetent cells.