A Bone Marrow-Derived APC in the Gut-Associated Lymphoid Tissue Captures Oral Antigens and Presents Them to Both CD4+ and CD8+ T Cells

Abstract

We have previously reported that feeding OVA to C57BL/6 mice can lead to a weak CTL response that is dependent on CD4+ T cell help and is capable of causing autoimmunity. In this study, we investigated the basis of the class I and class II-restricted Ag presentation required for such CTL induction. Two days after feeding OVA, Ag-specific CD4+ and CD8+ T cells were seen to proliferate in the Peyer’s patches and mesenteric lymph nodes. Little proliferation was evident in other lymphoid tissues, except at high Ags doses, in which case some dividing CD4+ T cells were observed in the spleen and peripheral lymph nodes. Using chimeric mice, the APC responsible for presenting orally derived Ags was shown to be derived from the bone marrow. Examination of the Ag dose required to activate either CD4+ or CD8+ T cells indicated that a single dose of 6 mg OVA was the minimum dose that consistently stimulated either T cell subset. These data indicate that oral Ags can be transported from the gut into the gut-associated lymphoid tissue, where they are captured by a bone marrow-derived APC and presented to both CD4+ and CD8+ T cells.

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

“…In models of orally fed Ag, both mesenteric LNs and Peyer's patches were shown to be the predominant sites of Ag presentation (58 -61), and critical for the induction of oral tolerance (59,62). To a lesser extent, oral Ag delivery has also been shown to induce clonal expansion of Ag-specific T cells in the spleen and, in cases in which high doses of Ag are administered, even in peripheral LNs (61,63,64). In our study, only very minute populations of donor transgenic T cells underwent proliferation in distal LNs.…”

Roundtrip Ticket for Secretory IgA: Role in Mucosal Homeostasis?

“…The phenotypic analysis of DC within tissues of the gastrointestinal tract has identified a plethora of distinct subtypes with different spatial distribution and effector functions (22). Intestinal DC have been shown to play a central role in the induction of local productive responses (23) or oral tolerance in the absence of any exogenous inflammatory signal (24). Populations of mouse DC isolated from Peyer's patches, lamina propria, mesenteric lymph nodes (MLN), and even lung have a propensity to induce Th2 responses in T cell priming assays in vitro (25,26).…”

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

“…Several lines of investigation suggest that luminal Ag is transferred across specialized epithelial cells, called M cells overlying PP (1), and passed to APC in the subepithelial dome, germinal center, and interfollicular regions (2)(3)(4)(5). However, PP and M cells do not appear to be required for oral Ag uptake, and M cells or epithelial cells are unlikely to directly present MHC class II-restricted Ags themselves (6,7). Ag absorbed through the intestine is also delivered to T cells at sites outside the PP.…”