Factors affecting ThTh differentiation

CD8 T-cells are predestined to mature into cytotoxic T-cells. However, Th1 and Th2 cells develop from a common CD4 T-cell precursor. Differentiation of precursor Th-cells is determined by genetic and environmental factors influential at the time of T-cell antigen recognition. Several factors influencing Th1/Th2 polarization have been proposed and demonstrated, but the most potent factor is the local cytokine milieu present at the time of T-cell activation.

The most potent cytokine promoting development of the Th1 phenotype is IL-12 in the absence of IL-4 (Trinchieri and Gerosa, 1996). Macrophages and professional antigen-presenting cells, such as dendritic cells, secrete IL-12 in response to bacteria, bacterial products and intracellular parasites. IL-12 is extremely potent in promoting Th1-biased differentiation by direct influences on the Th-cells. The most potent Th2-promoting stimulus is IL-4 in the absence of IFN-7, but the initial source of polarizing IL-4 is not established (Ricci et a/.,

Th1-cell

Augment

Activation of uncommitted CD4 T-cell

Th2-cell

Augment

Th1-cell

Augment

Activation of uncommitted CD4 T-cell

Th2-cell

Augment

Th1-cell

Th2-cell

Macrophage activation

B-cell secretion of IgG1 and IgG3

B-cell secretion of IgE

T Mast cells t Eosinophils, recruitment and activation

Fig. 1.8. Schematic representation of CD4 Th-cell differentiation into Th1 or Th2 cells. Th1 differentiation leads to macrophage activation and the secretion of opsonizing IgG. Th2 differentiation results in IgE secretion, mastocytosis and eosinophilia.

Th1-cell

Th2-cell

Macrophage activation

B-cell secretion of IgG1 and IgG3

B-cell secretion of IgE

T Mast cells t Eosinophils, recruitment and activation

  1. 1.8. Schematic representation of CD4 Th-cell differentiation into Th1 or Th2 cells. Th1 differentiation leads to macrophage activation and the secretion of opsonizing IgG. Th2 differentiation results in IgE secretion, mastocytosis and eosinophilia.
  2. Environmental and/or genetic factors may induce IL-4 secretion during activation of CD4 cells; a small specialized subset of CD4 T-cells known as CD4 NK1.1 secrete IL-4 on stimulation, and antigen presentation by B-cells can stimulate Th2 differentiation (Mason, 1996).

Although the cytokine microenvironment is the most potent determinant of Th1/Th2 polarization, Th1/Th2 differentiation is also influenced by complex interactions between antigen dose, TCR and MHC antigen affinities. Influential antigenic properties include the nature of the antigen, with viruses and bacteria favouring Th1 differentiation and helminths Th2. Th2 differentiation appears to be promoted by the small, highly soluble proteins characteristic of allergens. Some important allergens (house dust-mite allergen Der p1, subtilisin and papain) are proteases, and it is suggested that this favours Th2 differentiation, because helminths secrete proteases to aid tissue penetration. It is apparent that many factors influence Th1/Th2 differentiation, but it is highly unlikely that any single criterion is the sole determinant of Th-cell differentiation, because this would be quickly perverted by rapidly evolving pathogens. The complex matrix of factors that eventually determine Th0, Th1 or Th2 polarization is probably an immunological evolutionary adaptation to reduce the scope for pathogen interference.

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