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Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction - PubMed

  • ️Thu Jan 01 1998

Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction

C Kurts et al. J Exp Med. 1998.

Abstract

Naive T cells recirculate mainly within the secondary lymphoid compartment, but once activated they can enter peripheral tissues and perform effector functions. To activate naive T cells, foreign antigens must traffic from the site of infection to the draining lymph nodes, where they can be presented by professional antigen presenting cells. For major histocompatibility complex class I-restricted presentation to CD8+ T cells, this can occur via the cross-presentation pathway. Here, we investigated the conditions allowing antigen access to this pathway. We show that the level of antigen expressed by peripheral tissues must be relatively high to facilitate cross-presentation to naive CD8+ T cells. Below this level, peripheral antigens did not stimulate by cross-presentation and were ignored by naive CD8+ T cells, although they could sensitize tissue cells for destruction by activated cytotoxic T lymphocytes (CTLs). Interestingly, CTL-mediated tissue destruction facilitated cross-presentation of low dose antigens for activation of naive CD8+ T cells. This represents the first in vivo evidence that cellular destruction can enhance access of exogenous antigens to the cross-presentation pathway. These data indicate that the cross-presentation pathway focuses on high dose antigens and those released during tissue destruction.

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Figures

Figure 1
Figure 1

OVA expression by pancreatic islets of transgenic mice. RIP-mOVA mice (A), RIP-OVAlo mice (B), and RIP-OVAhi mice (C) were stained for OVA using a rabbit anti-OVA antiserum, obtained by immunizing rabbits with whole OVA (Grade V; Sigma Chemical Co., St. Louis, MO) and horseradish peroxidase–conjugated swine anti–rabbit Ig (DAKO, A/S, Glostrup, Denmark) as previously described (10). Note that secreted OVA was very difficult to detect immunohistologically and could only be demonstrated in the RIP-OVAhi line. RIP-mOVA mice, which express a membrane-bound form of OVA in their islet, were included as a positive control to show that this technique efficiently detects OVA when it is not secreted.

Figure 3
Figure 3

Activated OT-I cells cause diabetes when adoptively transferred into RIP-OVAlo mice or RIP-OVAhi mice. OT-I cells were activated with antigen in vitro for 5 d and then 107 cells were adoptively transferred intravenously into adult RIP-OVAlo (solid line) or RIP-OVAhi (dashed line) mice. These mice were then monitored daily for induction of diabetes as measured by glucosuria. Islet destruction was confirmed by histological examination of pancreatic tissue sections from several of these mice. These data represent the compilation of five experiments.

Figure 2
Figure 2

Secreted OVA is cross-presented in the draining LNs of the pancreas when expressed at a sufficiently high dose. 5 × 106 OT-I cells were labeled with CFSE (11) and adoptively transferred intravenously into either RIP-OVAlo mice (A and B), RIP-OVAhi mice (C and D), or negative littermates (data not shown). 3 d later, the pancreatic (A and C) and inguinal (B and D) LN cells were analyzed by flow cytometry (11). As previously reported (11), negative littermates did not induce proliferation of OT-I cells (data not shown). Histograms were gated on CD8+CFSE+ cells.

Figure 4
Figure 4

Tissue destruction facilitates cross-presentation of low dose antigens. RIP-OVAlo mice were either left untreated (A and B) or injected with 5 × 106 OT-I cells activated as in Fig. 3 (C–H). 1 (G and H) or 4 d (A–F) later, mice were injected with CFSE-labeled cells (either 5 × 106 naive OT-I cells [A–D, G, and H] or 2 × 106 B6 CD8+ LN cells [E and F]). After a further 3 d, the pancreatic (A, C, E, and G) and inguinal (B, D, F, and H) LN cells were analyzed by flow cytometry. Histograms were gated on CD8+CFSE+ cells.

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