The role of small intestinal antigen‐presenting cells in the induction of T‐cell reactivity to soluble protein antigens: association between aberrant presentation in the lamina propria and oral tolerance

Abstract

The oral administration of soluble protein antigen results in profound immunological tolerance. However, the tissue location and function of antigen‐presenting cells (APC) that stimulate this response remain unclear. We have hypothesized that the properties of cells presenting antigen to naive T cells within the gut are involved, and therefore gut APC should stimulate T‐cell responses with different characteristics to those induced by other APC. To test this, we studied in vitro primary T‐cell responses following presentation of soluble protein antigen by cells from the Peyer's patches (PPC) and lamina propria (LPC) of the murine small intestine and the spleen (SPLC). Each APC population stimulated antigen‐specific proliferative responses with similar anamnestic characteristics; however, analysis of the cytokines produced revealed marked differences. Whereas SPLC stimulated the balanced production of T‐helper type 1 (Th1) and Th2 cytokines, PPC induced a profile consistent with the provision of T‐cell help for IgA production. Interestingly, presentation of antigen by LPC stimulated high levels of interferon‐γ (IFN‐γ) and transforming growth factor‐β (TGF‐β) in the absence of other cytokines [interleukin‐2 (IL‐2), IL‐4, IL‐5]. Evidence from analysis of cell activation and division within the cultures suggested that this profile may result from the preferential activation of CD8+ T cells by LPC; however, the lack of conventional CD4+ T‐cell cytokines indicated a defect in the normal function of these cells. Adoptive transfer of antigen‐pulsed LPC to syngeneic animals abrogated the induction of delayed‐type hypersensitivity (DTH) responsiveness, which followed a subsequent conventional antigen challenge further suggesting a role for lamina propria APC in tolerance induction.

Immunomodulatory dendritic cells in intestinal lamina propria

“…There are many APC such as DC in the mucosal LP, and we found that a substantial amount of orally administered protein antigen is taken up by APC in the LP, confirming previous findings of antigen loading at this site [17]. We now show directly that DC are likely to be responsible for this phenomenon and have characterized this population for the first time.…”

Murine Peyer’s Patches Favor Development of an IL-10-Secreting, Regulatory T Cell Population

“…PP dendritic cells are distinct from those isolated from other secondary immune tissue and may contribute to the development of IL-10-secreting CD45RB low CD4 ϩ T cells. Dendritic cells residing in different tissues induce distinct immune responses from T cells (7,8,23). For instance, repetitive stimulation using immature human dendritic cells leads to differentiation of nonproliferative, IL-10-producing T cells with the ability to suppress proliferation of Th1 cells in vitro (16) Inhibiting IL-4, IL-10, and TGF-␤ in vitro did not appear to affect the functional response of PP T cells, suggesting that the effector function of these cells is established in vivo and is not readily modulated.…”

“…In the neighboring intrafollicular region of the PP, dendritic cells of a more mature phenotype than those found in the subepithelial dome lie in close association with T cells (6). Ag presentation by PP dendritic cells in vitro promotes splenic T cells to secrete IL-4, IL-6, and IL-10, in contrast to the proinflammatory cytokine, IFN-␥, induced by splenic dendritic cells (7)(8)(9). Furthermore, PP dendritic cells themselves secrete IL-10, an indication that, within the PP, T cells may be exposed to Ag in the presence of IL-10 (9).…”

The State of CD4+ T Cell Activation Is a Major Factor for Determining the Kinetics and Location of T Cell Responses to Oral Antigen

“…However, if Ag crosses into subepithelial spaces as free peptide, it is possible that binding to class II MHC molecules occurs on basal surfaces exposed to underlying LP. Studies from Harper et al (57) suggest that DC in the LP may present oral Ag to local T cells. These and other data support the notion that oral Ag permeates the epithelial barrier where it is presented to resident LP T cells by local APC (14).…”