Role of T‐Cell Derived Cytokines in the Downregulation of Immune Responses in Parasitic and Retroviral Infection

Abstract

Parasitic infection is frequently accompanied by a downregulation in host cell-mediated immunity. Recent studies suggest that this modulation of helper T cells and effector cell function can at least in part be attributed to the action of a set of inhibitory cytokines produced by T lymphocytes as well as by a number of other cell types. The best characterized of these inhibitory lymphokines are IL-4, IL-10 and TGF-beta. Interestingly, both IL-4 and IL-10 are produced by the Th2 but not the Th1 subset of CD4+ helper cells. The former subset dominates in many situations of chronic or exacerbated parasitic infection and is thought to suppress Th1 function as a consequence of the cross-regulatory activity of these two cytokines. The latter hypothesis is supported by recent experiments demonstrating that mAb-mediated neutralization of IL-10 reverses suppressed IFN-gamma responses and/or disease susceptibility in mice with parasitic infections. In vivo neutralization of TGF-beta has also been reported to increase host resistance to parasite challenge. In addition to suppressing T-cell differentiation, function or proliferation, IL-4, IL-10 and TGF-beta each inhibit the ability of IFN-gamma to activate macrophages for killing of both intracellular and extracellular parasites. Moreover, the three cytokines are able to synergize with each other in downregulating these parasiticidal effects. Interestingly, each of the cytokines inhibits the production of reactive nitrogen oxides, an effector mechanism previously demonstrated to play a major role in parasite killing by activated macrophages. In the case of IL-10, this suppression of nitrogen oxide production appears to result from an inhibition of TNF-alpha synthesis leading to defective macrophage stimulation. While distant from parasites in their biology and phylogeny, some retroviruses also appear to induce an over-production in downregulatory cytokines which is closely associated with the onset of immunodeficiency. Thus, in an animal model involving infection of mice with LP-BM5 MuLV and in human HIV infection, Th2 (IL-10 and/or IL-4) cytokine synthesis is increased while Th1 (IFN-gamma and/or IL-2) cytokine production is suppressed. These observations suggest that cytokine-mediated cross-regulation may play a role in the pathogenesis of acquired immune deficiency disease, contributing both to the progression of retroviral infection and the increase in susceptibility to opportunistic infections and malignancy. Observations of similar cytokine cross-regulatory activities in organisms as diverse as helminths, protozoa and retroviruses predict that comparable mechanisms may operate in a wide variety of infectious diseases.

In vitro production of type 1 and type 2 cytokines by peripheral blood mononuclear cells from subjects coinfected with human immunodeficiency virus and Leishmania infantum.

“…25 During parasitic coinfection, release of IFN-␥ is probably down-regulated further by the suppressive action of IL-4. 26 It has been proposed that prolonged anti-leishmanial therapy in an immunocompetent host may favor a reverse switch from a Th2 to a Th1 response, thus promoting recovery. 17,27,28 Furthermore, sodium stilbogluconate seems to require endogenous production of IFN-␥ to function optimally.…”

In vivo expression of recombinant pregnancy‐specific glycoprotein 1a induces alternative activation of monocytes and enhances Th2‐type immune response

“…T helper (Th) cells can be divided into Th1 and Th2 cells, according to their cytokine profile upon antigenic stimulation [1,2]. The Th1 subset produces high levels of IL-2 and IFN-+ causing monocyte/macrophage (Mo) activation, which is important for the protection against intracellular pathogens.…”

Interferon‐γ Production in Antigen Specific T Cell Response: Quantitation of Specific mRNA and Secreted Protein

“…The former secrete predominantly mediators of the delayed type of hypersensitivity such as IL-2, tumour necrosis factor-b (TNF-b) and interferon gamma (IFN-g) whereas Th2 cells secrete more IL-4, IL-5, IL-10 and TGF-b and provide help for antibody production [3]. Lymphocyte proliferation assay reflects mainly Th1 cell activation and is actually inhibited by the products of Th2 type cells [4].…”