IL10 and Th1Th2 Effector Choice

IL-10 was initially characterized as a Th2-specific cytokine that inhibits IFN-y secretion by Th1 cells.1 Because IL-10 can also be produced by activated antigen presenting cells (APC) (macrophages, dendritic cells (DC) and B lymphocytes2-4) it was regarded as a candidate factor that could positively influence the development of Th2 cells and negatively regulate differentiation of Th1 cells. However, experimental data have failed to support this simplistic view of IL-10's effect on Th1/T2 polarization. As anticipated, when primed with model antigens (Ag) or pathogens known to induce Th1-type responses, IL-10-/- animals display highly augmented immune responses frequently associated with detrimental Th1-mediated pathology. For example, IL-10-/- mice infected with Toxoplasma gondii,5 Plasmodium chaubudi,6 or certain strains of Trypanozoma cruzi,7 have greatly elevated levels of IFN-y, IL-12 and TNF-a and reduced parasitemia, but substantially increased risk of death from a toxic shock-like syndrome compared to wild-type (WT) controls. Unexpectedly, however, IL-10-/- mice also display enhanced Th2 responses when either challenged with allergens or exposed to Th2-type pathogens.8-10 Together these findings show that IL-10 acts as a general negative regulator of CD4-dependent immune responses rather than a polarizing cytokine that influences Th1/Th2 commitment.

The inhibitory effect of IL-10 stems from its ability to down-regulate antigen-presenting functions of both macrophages and DC, the primary sources of Ag/MHC complexes during T cell priming.11,12 The indirect influence of IL-10 on Th cells has been further supported by the analysis of IL-10R expression. IL-10R is expressed by most hematopoietic cells.13 However, while its expression is down-regulated on activated CD4+ T lymphocytes,14 activation of monocytes is associated with an increase in IL-10R levels,15 providing the molecular basis for the IL-10 responsiveness of the latter but not the former cell population.

In the context of Th effector choice, an important aspect of IL-10 effects on APC is its ability to inhibit not only the expression of MHC class II and costimulatory molecules but also the secretion of cytokines and chemokines.12,16 Although the latter effect of IL-10 is not selective and affects most of the soluble mediators produced by activated macrophages and DC, its primary consequence is down-regulation of the Th1 development, because many of the monokines (e.g., IL-12, IL-18, IL-23 and IL-27) are IFN-y-inducible cytokines required for optimal Th1 differentiation.17 For the same reason, IL-10-treated macrophages or DC appear to be promoting Th2 development.18 In contrast to this differential effect on Th1/Th2 differentiation, the accumulation of mature Th1 and Th2 effectors at the site of inflammation can be equally affected by IL-10 since it down-regulates the production of both CC and CXC chemokines.19,20 In addition to inhibiting the production of cytokines and chemokines, IL-10 also enhances the expression of their natural antagonists by increasing the expression of either decoy (e.g., IL-1RA and chemokine receptors)21,2 or soluble (e.g., p55 and p75 TNFR) receptors23,24 that in turn potentiate IL-10's down-modulatory effects on APC functions.

Different IL-10-producing DC populations (e.g., from Peyer's patches25 and liver26) have been associated with the development ofTh2 responses. Recently, these observations have been extended by the findings that IL-10 is required for optimal development of Th2 cells by the CD8-CD11c+ subset of splenic DC.27 However, since IL-10 may selectively induce apoptosis of CD8a+ CD11c+ cells,27 this Th2 priming by IL-10 appears to be a result of a loss of

Figure 1. IL-10 as modulator of innate and adaptive immunity.

IL-12-producing DC and a subsequent lack of Th1 differentiation. In addition, while the particular DC subsets were not analyzed, naïve and Trichinella spiralis-infected IL-10 knockout (KO) mice display higher number of CD11c+ DC in mesenteric lymph nodes when compared to WT animals.28 Autocrine IL-10 has been shown to prevent spontaneous maturation of human DC in vitro and to limit LPS and CD40-induced maturation.29

While initially specifically associated with Th2 cells, the expression of IL-10 is now found in other Th subsets as well. When cultured in the presence of IL-10, murine bone marrow-derived DC promote development of IL-10+ CD4+ Treg lymphocytes.30 Moreover, similar to human Th1 cells, 31 murine Th1 lymphocytes may also coexpress IL-10. For example, "classical" mu-rine Th1 immune responses following infection with different intracellular pathogens (e.g., Brucella abortus, Borrelia burgdorferi, Leishmania major, T. gondii) include not only IFN-y+ CD4+ cells but also "nonclassical" Th1 lymphocytes that concomitantly produce IFN-y and IL-10 32-35

Thus, although the effect of IL-10 on Th1/Th2 effector choice is indirect and very complex (Fig. 1), IL-10 and IL-10R still represent attractive therapeutic targets for the manipulation of APC function aimed at both promoting or/and suppressing development of different types of CD4-dependent immune responses.36,37

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