Mechanisms of oral tolerance

The primary mechanisms by which oral tolerance is mediated include deletion, anergy and active cellular suppression with the determining factor being the dose of antigen fed (Figure 2). Low doses favor active suppression mediated by the induction of regulatory T cells in the gut-associated lymphoid tissue, such as Peyer's patches, which then migrate to the systemic immune system. When higher doses of antigen are fed, clonal anergy or deletion results.

Active cellular suppression of immune responses has been studied extensively over the years and has remained ill-defined due to difficulties in cloning sup-

Oral administration of antigen

Gut-associated lymphoid tissue

Gut-associated lymphoid tissue

Active suppression

Clonal anergy Clonal deletion

Oral tolerance

Figure 2 Mechanisms of oral tolerance.

pressor cells and defining their mechanism of action. More recently, it appears that one of the primary mechanisms of active cellular suppression is via the secretion of suppressive cytokines such as tumor growth factor [3 (TGFp), interleukin 4 (IL-4) and IL-10 after antigen-specific triggering. In this sense the GALT is unique as it favors the induction of cells which secrete these cytokines, Tn2 as opposed to Th1 cells and T cells which secrete TGF(3, a potent immunosuppressive and antiinflammatory cytokine. T Cells in lymphoid organs drained by mucosal sites secrete IL-4 as a primary T cell growth factor, whereas those drained by nonmucosal sites secrete IL-2. Oral tolerance has often been demonstrated by a decreased delayed-type hypersensitivity (DTH) response to the fed antigen and it is known that DTH is a Th1 response inhibited by IL-4-producing T,,2 cells. TGFfS plays an important role in local function of the gut as it serves as a switch factor for IgA production in the mucosa and may also be involved in the homing mechanism of the cells to high endothelial venules. TGFp is produced by both CD4~ and CD8+ GALT-derived T cells and is an important mediator of the active component of oral tolerance. Mice that are TGFp-deficient have inflammation that affects multiple organ systems, demonstrating the importance of this cytokine in maintaining immune homeostasis. TGFp is also associated with natural recovery from experimental autoimmune encephalomyelitis (EAE), and regulatory cells which suppress certain forms of inflammatory colitis act via secretion of TGFfJ.

We cloned TGF(3-secreting myelin basic protein (MBP)-specific CD4+ cells from the mesenteric lymph nodes of SJL mice. These clones were structurally identical to TH1 disease-inducing clones in T cell receptor (TCR) usage, major histocompatibility com-

Table 1 T cell subsets

Cytokine profile

Growth factors IL-2 Functions

Help DTH/lgG2a

Suppression TH2

plex (MHC) restriction and epitope recognition but suppressed rather than induced disease. We have also recently cloned TGFp-secreting CD4+ cells from orally tolerized (low dose fed) MBP TCR transgenic mice. These latter clones do not secrete IL-2, interferon y (IFNy), IL-4 or IL-10 and their primary growth factor is IL-4. Thus, CD4+ cells which primarily produce TGF(3 appear to be a unique T cell subset with both mucosal T helper function and downregulatory properties for Tnl and other immune cells. In contrast to TH1 and TH2 cells, these cells provide help for immunoglobulin A (IgA) production. These TGF3-secreting T cells have been termed TH3 cells (Table 1) and have also been observed in multiple sclerosis (MS) patients orally dosed with myelin. TGFp-secreting TH3 clones grow poorly, which has thus far hampered rapid characterization of these cells. The fact that Tn3 cells do not proliferate well may also account for their relative resistence to deletion as compared to Tnl and TH2 cells following oral administration of high-dose antigen to ovalbumin (OVA) TCR receptor transgenic mice.

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