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

Abstract

Current models suggest that inductive immune responses to enteric Ag are initiated in Peyer’s patches (PP) and mesenteric lymph nodes (MLN) followed by migration of activated, memory-like CD4+ T cells to extralymphoid sites in the intestinal lamina propria (LP). The resultant immune system contains both naive and activated T cells. To examine the differential responses of naive and memory-like T cells to oral Ag, bone marrow chimeras (BMC) were generated. Irradiated BALB/c hosts were reconstituted with a mix of DO11.10 × RAG-1−/− and BALB/c bone marrow. In unprimed DO11.10 and BMC models, LP and PP DO11.10 T cells responded to oral Ag with similar kinetics. Responses of activated, memory-like T cells to oral Ag were examined in thymectomized BMC 60 days after i.p. immunization with OVA peptide in Freund’s adjuvant (OVA323–339/CFA). Results indicate that i.p. OVA323–339/CFA generated a high proportion of memory-like CD45RBlow DO11.10 T cells in peripheral lymphoid (40%) and intestinal LP (70%) tissue. Previously activated DO11.10 T cells in the LP responded to oral Ag earlier and at 50% higher levels compared with memory CD4+ T cells localized to PP tissue. These data indicate that responses to oral Ag in antigenically naive animals are initiated in PP whereas in Ag-experienced animals LP T cells respond earlier and more vigorously than cells in PP. Taken together, these data suggest that previous activation alters the hierarchy of T cell responses to oral Ag by enhancing the efficiency of LP T cell activation.

The role of CD4+ and CD8+ T cells on antibody production by murine Peyer's patch cells following mucosal presentation of Actinomyces viscosus

“…The results of the present study showed that high levels of anti‐ A. viscosus antibodies, predominantly the IgA isotype, were produced by PP cells taken from orally immunized mice. These results are in agreement with previous studies that oral immunization induced a mucosal immune response initiated in the PP in mice (6, 7). Furthermore, PP dendritic cells, which produce cytokines such as IL‐10, may preferentially help in the activation of Th2 cells, and hence in the generation of IgA + B cells (3, 10).…”

Co‐administration of CD40 agonistic antibody and antigen fails to overcome the induction of oral tolerance

“…It has been reported that antigen‐specific T cells proliferate primarily in PPs and MLNs in response to oral antigen 22,23 . It seems reasonable to assume that providing costimulatory molecules on APCs would enhance such activation and/or proliferation of antigen‐specific T cells.…”

T‐cell activation in the intestinal mucosa

“…Upon activation following CD3ε ligation, murine CD8 + IELs produce interferon‐γ (IFN‐γ) more rapidly and to greater levels than CD8 + lymph node cells (15). Moreover, the activation state of CD4 + intestinal lamina propria cells also appears to reflect the nature of the intestinal response to oral antigens (20).…”