DESNUTRICIÓN

The most important factor determining the differentiation into Thl or Th2 cells, is the initial presence of specific cytokines, most of which are those characteristic cytokines produced by the T cell subsets themselves (reviewed in: Seder et al. 1994; Reiner et al.

Thus for example, many experiments have shown that IL-4 is required for differentiation of Th2 cells since the presence of IL-4 promoted Th2 development and the depletion of IL-4 prevented Th2 priming both in vivo (Heinzel et al. 1989; Sadick et

al. 1990; Chantelain et al. 1992; Romani et al. 1992; Gross et al. 1993) and in vitro (Le Gros et al 1990; Seder et al. 1991, 1992). In addition, IL-4 deficient mice were defective in Th2 cytokine responses (Kopf et al. 1993; Kanagawa et al. 1993).

Recently however, a number of studies have shown that Th2 differentiation can occur in the absence of IL-4, including in IL-4 deficient mice (von der Weid et al. 1994; Noben-Trauth et al. 1996). There is also evidence to suggest that in the presence of IL-4 neutralising antibodies, PB derived CD45RA T cells were found to produce IL-4 when stimulated with anti-CD3 in combination with either anti-CD28 or IL-lp (Brinkmann et al. 1996; Kalinski et al. 1995). This suggests the existence of other cytokines capable of priming for Th2 cells. One such cytokine that has been suggested is IL-13, since it has many features in common with IL-4, such as inducing proliferation and differentiation of B cells; and Ig class switching and secretion of IgE (Minty et al. 1993; Cocks et al. 1993; Punnonen et al. 1993; Defrance et al. 1994). There is also evidence that both cytokines may signal via the IL-4 receptor, since the same antagonist (IL-4 cytokine mutant) was found to inhibit the IL-4 and IL-13 induced IgE production and B cell proliferation (Aversa et al. 1993) and both cytokines can also phosphorylate the IL-4 receptor (Smertz-Bertling et al. 1995). In addition, IL-13 is also found at increased levels at sites of allergen challenge in asthmatic patients (Huang et al. 1995), a condition normally associated with Th2 cytokines (see section 1.6: Association of upper respiratory tract viruses in asthma).

IL-2 is required by both Thl and Th2 cells as a growth factor (Femando-Botran et al. 1988) and also acts as differentiation factor for Th2 cells (Ben-Sasson et al. 1990a; Femando-Botran et al. 1988; Le Gros et al. 1990).

IL-12 can influence Thl priming by it’s ability to increase production of IFNy by numerous cells such as NK cells (Chan et al. 1991; Gazzinelli et al. 1993; Tripp et al.

1993), freshly isolated resting or activated PB T cells (Chan et al. 1991; Kubin et al. 1994), Thl clones (Murphy et al. 1994; Manetti et al. 1994), ThO clones (Manetti et al.

1994), as well as a transient production in Th2 clones (Yssel et al. 1994; Manetti et al. 1994). Consequently in a number of studies, the Thl priming effects of IL-12 have been shown to be dependent on the presence of IFNy, since neutralisation of IFNy prevented priming for Thl cells in vitro (Seder et al. 1993; Macatonia et al. 1993; Schmitt et al. 1994a). Direct effects of IL-12 are also possible, since in some cases, the neutralisation of IFNy in vivo did not affect Thl priming induced by IL-12 (McKnight et al. 1994b;

Via et al. 1994) and could occur in IFNy deficient mice (Wang et al. 1994b). One study showed that the effects of IL-12 were dependent on IFNy only in APC-independent systems, and it was suggested that IFNy may provide a costimulatory cofactor for IL-12 which can also be provided directly by APC (Seder et al. 1993). However, there are also a number of in vivo studies that show that neutralisation of IFNy can inhibit the effects of IL-12 (Finkelman et al. 1994; Wynn et al. 1994; Oswald et al. 1994; Heinzel et al. 1993), suggesting that some other factor besides the presence of APC can influence the IFNy dependence of IL-12 on Thl priming. In addition to IFNy, IL-12 can synergise with many other factors such as IL-2, CD28, B7, phorbol dieAters,PHA and anti-CD3, to costimulate Thl differentiation and proliferation of established Thl cells (Wolf et al. 1991; Kubin et al. 1994; Chan et al. 1991; Murphy et al. 1994). IL-12 may also contribute to Thl mediated effector functions by it’s ability to increase the cytotoxic activity of T cells and NK cells (Chehimi et al. 1993).

Independently of its role in mediating the effects of IL-12, the requirement for IFNy in priming of T cells is also unclear. Thus in some systems, it’s presence in priming cultures can result in the preferential expansion of Thl cells (Gajewski et al. 1989) and inhibition of Thl priming was observed in vivo either in the presence of neutralising

antibodies to IFNy (Scott 1991; Chantelain et al. 1992; Belosevic et al. 1989) or in mice with a disruption of IFNy gene (Wang et al. 1994a). In other studies however, Thl priming was observed in the presence of neutralising antibodies to IFNy, in vitro (Seder

et al. 1992) or in IFNy gene or receptor deficient mice (Schijns et al. 1994; Swihart et al, 1995). Regardless of it’s direct requirement for priming, IFNy can influence development of Thl cells indirectly by enhancing the production of other Thl promoting cytokines such IL-12 (Trinchieri et al. 1992) and as discussed above, may also act as a costimulatory factor for IL-12 induced Thl priming (Wenner et al. 1996).

Other cytokines capable of influencing the development of a Thl phenotype, include IFN a and TGFp. IFN a has been shown to increase the production of Thl cytokines (Finkelman et al. 1991; Recht et al. 1991); increase the frequency of CD4 T cells producing IFNy and with cytolytic activity (Brinkmann et al. 1993; Parronchi et al.

1992); reduce the ability to help B cells, particularly for the production of IgE (Brinkmann et al. 1992; Finkelman et al. 1991; Pene et al. 1988); and synergise with IL- 12 to inhibit IL-4 production (Wenner et al. 1996). TGFP has been shown to promote the development of Thl cells (Swain et al. 1991; Spaccapelo et al. 1995) and CD8 T cell differentiation (Suda et al. 1992). However TGFp can also enhance Th2 responses in

vivo (Barral-Netto et al. 1992) such as the production of IgA by B cells (Coffman et al. 1989) and may have inhibitory effects on both T cell and B cell activation (Kehrl et al. 1986, Fontana et al. 1989).

The discovery of a new cytokine with similar biological functions to IL-12 and which can also synergise with IL-12 to induce IFNy production (Okamura et al. 1995), suggests that other unidentified cytokines may exist that could provide the missing links in the above experiments.