TGFp and the immune response

TGFp exhibits bifunctional properties, depending on the type and state of cells as well as the presence of other cytokines (Figure 2). TGFp, has been shown to completely suppress the proliferative response of CD4+ or CD8+ T cell clones to IL-2 or phorbol ester/ionophore. TGFp blocks the generation of both cytotoxic T cells in allogeneic mixed lymphocyte cul-

- Lymphocyte growth and differentiation

Inhibition

Promotion

T and B cell proliferation NK activity

IgG and IgM production TNFa and IL-1 effects Inflammatory reaction NO production

Apoptosis of T, B cells and microglia

Extracellular matrix synthesis IL-1 and TNFa production IL-6 production CD8* T cell growth Fibroblasts

B cells carrying EB virus IgA secretion

C3 secretion and C3 receptor expression ' Oligodendrocyte differentiation

Figure 2 The bifunctional properties of TGFß.

tures and IL-2-induced cytokine-activated killer cells and natural killer (NK) cells. It has become clear that TGFp downregulates both cell-mediated and humoral immunity. TGFp probably exerts its immunosuppressive effects by regulating the expression of other cytokines, e.g. interferon y (IFNy). TGF(B inhibits the production of both IFNy and IL-4 in mitogen-activated human blood mononuclear cells.

TGFp administered systemically has profound effects on models of organ-specific inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. The pronounced suppression of the localized immune responses is not associated with any significant generalized immune suppression. These observations could reflect resistance to suppression of resting lymphocytes, but increased susceptibility of activated T lymphocytes. This may also explain the apparently opposing effects of TGFp on cells at different times in their life cycle: TGFp is released early and functions in many capacities to promote inflammation based on its stimulating effects on immature monocytes and T cells. Once these cells differentiate and become activated, they become susceptible to pheno-typic modulation and functional inhibition by TGFp. Under normal conditions, this transition from pro-to anti-inflammatory responsiveness occurs with minimal disruption of host cell and tissue homeostasis.

TGFp-dependent suppression of antigen-induced T cell growth involves several distinct pathways which include 1) the direct inhibition of mitosis in the late Gi phase of the cell cycle, and 2) regulation of transcription of the early growth factor-dependent c-myc gene and of the transferrin receptor. TGFp may also suppress clonal expansion indirectly by inducing synthesis of IL-1 receptor antagonist that has the capacity to abort IL-1-dependent responses.

TGFp also influences maturation of T helper cells in different ways. TGFp suppresses the development of IL-4-producing T lymphocytes and stimulates the generation of IFNy-secreting T cells in vitro. In contrast, in an in vivo murine model, administration of TGFp at the time of infection with Leishmania ama-zonensis or L. braziliensis induced increased mRNA levels for IL-4 and decreased levels for IFNy.

CD4+ and CD8+ T lymphocytes are differentially susceptible to TGFp: inhibition of CD4+ T cells is nearly complete, whereas TGFp is considerably less inhibitory and may even promote CD8' cell growth. Resistant CD8+ T cells synthesize cytokines including IL-4 and IL-10 which have additional immunosuppressive properties. Under appropriate conditions, TGFp appears to foster the generation of inhibitory feedback molecules and apparently works in concert with them to reverse immune processes. TGFP contributes to the shift toward TH2-type responses through direct and lL-10-mediated pathways. TGFp can induce apoprosis in cultured uterine epithelial cells, hepatoma cells, gastric carcinoma cells, myeloid leukemia cells, resting B cells and hepato-cytes in vitro and in vivo.

TGFp can inhibit proliferation and immunoglobulin (Ig) production by B cells. However, in the presence of an adequate combination of activators, e.g. antigen and T cell help, the inhibitory effects of TGFp are abrogated and large numbers of IgA' cells can be produced in Peyer's patches along the small intestine. Which cells produce the TGFp involved in regulation of IgA switching by inducing germline a-transcripts and how it is regulated remains to be settled.

TGFp is known to induce its own production and secretion. The autoinduction of TGFp, transcription is mediated by AP-1 (Jun-Fos) binding sites in the TGFp, promotor. By this mechanism, TGFp activity might become persistent, resulting in deleterious effects.

An inflammatory process in the brain requires bidirectional interactions of the immune and nervous system. Expression of TGFp is highly regulated in I" cells and is probably an important component in the molecular interaction between the immune and nervous systems. Glucocorticoids cause a significant decrease of TGFPi mRNA levels in glial cells but not T cells, indicating that TGFp,-regulatory pathways can be utilized to affect the functions of neural and immune cells. Microglia, the macrophages of the central nervous system (CNS), are positive for TGFp, mRNA and release TGFp,.

TGFp has immunosuppressive functions within the CNS. The target cells of this action are still unknown. TGFp, selectively induced apoptosis of microglia, but not astrocytes and oligodendrocytes. Bcl-2 oncoprotein was mainly expressed in microglia, indicating that TGFp,-mediated microglial apoptosis was regulated by a bcl-2-inde-pendent mechanism.

Overproduction of nitric oxide (NO) by glial cells, but not by infiltrating mononuclear cells, can be a major cause of target tissue damage in autoimmune diseases such as FAE and multiple sclerosis ; MS). TGFp has been shown to inhibit NO production by microglia. Astrocytes secrete both the active and latent form of TGFp2. Exogenous administration of TGFp could beneficially influence the course of such diseases. TGFp has also been shown to suppress rat astrocyte autoantigen presentation, and antagonizes hyperinduction of major histocompatibility complex (MHC) class II antigen induced by IFNy or TNF«.

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