Tryptophan degradation to control T-cell responsiveness

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In a recent Review1xTryptophan catabolism and T-cell tolerance: immunosuppression by starvation?. Mellor, A.L. and Munn, D.H. Immunol. Today. 1999; 20: 469–473Abstract | Full Text | Full Text PDF | PubMed | Scopus (434)See all References1, Mellor and Munn discuss the evidence that tryptophan availability may have an impact on T-cell responses. They propose that cells expressing indoleamine 2,3-dioxygenase (IDO) inhibit T-cell proliferation via degradation of tryptophan. Withdrawal of tryptophan via activation of IDO in monocytes/macrophages was shown to reduce T-cell activity in vivo2xPrevention of allogeneic fetal rejection by tryptophan catabolism. Munn, D.H. et al. Science. 1998; 281: 1191–1193Crossref | PubMedSee all References2. Our data, and that from other groups, support this conclusion and suggest that IDO activation could be of much broader relevance with respect to loss of T-cell responsiveness3xInduction of tryptophan degradation in vitro and in vivo: a gamma-interferon-stimulated activity. Byrne, G. et al. J. Interferon Res. 1986; 6: 389–396Crossref | PubMedSee all References, 4xHuman macrophages degrade tryptophan upon induction by interferon-gamma. Werner, E.R. et al. Life Sci. 1987; 41: 273Crossref | PubMed | Scopus (122)See all References, 5xDecreased serum tryptophan in patients with HIV-1 infection correlates with increased serum. Fuchs, D. et al. J. Acquired Immune Defic. Syndr. 1990; 3: 873–876PubMedSee all References, 6xWeight loss in patients with hematological neoplasias is associated with immune system stimulation. Denz, H. et al. Clin. Invest. 1993; 71: 37–41Crossref | PubMed | Scopus (49)See all References, 7xDegradation of tryptophan in patients with systemic lupus erythematosus. Widner, B. et al. Adv. Exp. Med. Biol. 1999; 467: 571–577Crossref | PubMedSee all References, 8xGasse, T. et al. : 351–382See all References.IDO is found in various cells and tissues including peripheral blood-derived-monocytes/macrophages, and its expression and activity is increased upon stimulation of cells with T helper 1 (Th1)-type cytokines such as interferon γ or tumour necrosis factor α (3xInduction of tryptophan degradation in vitro and in vivo: a gamma-interferon-stimulated activity. Byrne, G. et al. J. Interferon Res. 1986; 6: 389–396Crossref | PubMedSee all References, 4xHuman macrophages degrade tryptophan upon induction by interferon-gamma. Werner, E.R. et al. Life Sci. 1987; 41: 273Crossref | PubMed | Scopus (122)See all References). Accordingly, increased enzymatic degradation of tryptophan is found in vivo in diseases that are associated with chronic stimulation of Th1-mediated immunity, such as HIV-1 infection5xDecreased serum tryptophan in patients with HIV-1 infection correlates with increased serum. Fuchs, D. et al. J. Acquired Immune Defic. Syndr. 1990; 3: 873–876PubMedSee all References5, malignant diseases6xWeight loss in patients with hematological neoplasias is associated with immune system stimulation. Denz, H. et al. Clin. Invest. 1993; 71: 37–41Crossref | PubMed | Scopus (49)See all References6 and autoimmune disorders (e.g. systemic lupus erythematosus)7xDegradation of tryptophan in patients with systemic lupus erythematosus. Widner, B. et al. Adv. Exp. Med. Biol. 1999; 467: 571–577Crossref | PubMedSee all References7. Such patients frequently present with subnormal amounts of tryptophan in body fluids, while in parallel, tryptophan metabolites such as kynurenine and quinolinic acid accumulate8xGasse, T. et al. : 351–382See all References8. Moreover, the degradation of tryptophan positively correlates with indicators of immune activation in macrophages, such as neopterin and soluble cytokine receptors, thus confirming that cytokines increase IDO activity5xDecreased serum tryptophan in patients with HIV-1 infection correlates with increased serum. Fuchs, D. et al. J. Acquired Immune Defic. Syndr. 1990; 3: 873–876PubMedSee all References, 6xWeight loss in patients with hematological neoplasias is associated with immune system stimulation. Denz, H. et al. Clin. Invest. 1993; 71: 37–41Crossref | PubMed | Scopus (49)See all References, 7xDegradation of tryptophan in patients with systemic lupus erythematosus. Widner, B. et al. Adv. Exp. Med. Biol. 1999; 467: 571–577Crossref | PubMedSee all References, 8xGasse, T. et al. : 351–382See all References. Interestingly, the above-mentioned diseases are not only characterized by phenomena of immune activation but also by acquired loss of T-cell responsiveness to antigenic stimulation, as indicated by reduced skin test reactivity or impaired T-cell proliferation in response to antigenic challenge in vitro9xEndogenous release of interferon-gamma and diminished response of peripheral blood mononuclear cells to antigenic stimulation. Fuchs, D. et al. Immunol. Lett. 1989; 23: 103–108Crossref | PubMed | Scopus (82)See all References9.It appears that low tryptophan levels or increased concentrations of its degradation products may be directly involved in diminished T-cell responsiveness in the diseases mentioned above. In such patients, serum tryptophan concentrations are often less than 50% of those observed in normals. It will be most striking to see whether this is sufficient to diminish T-cell responsiveness, and to investigate the underlying mechanism (e.g. the limited availability of the essential amino acid tryptophan or antiproliferative effects of tryptophan metabolites towards T cells) responsible for this phenomena.