Skip to main content

OPINION article

Front. Immunol., 10 February 2014
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research Topic Tumor Cell/Dendritic Cell Interactions and the Influence of Tumors on Dendritic Cell-mediated Anti-Tumor Immune Responses and Dendritic Cell-Based Tumor Immunotherapies View all 18 articles

On the role of dendritic cells versus other cells in inducing protective CD8+ T cell responses

  • Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland

Dendritic cells (and/or macrophages) are key transporters of antigen from extralymphatic tissue to secondary lymphatic organs. The phagocytized antigen is presented via MHC class II but not via class I, except for infections by intracellular viruses, bacteria, etc. (14).

Class II-negative cells (e.g., fibroblasts) that get drained to secondary lymphatic organs (including spleen) induce MHC class I restricted CD8 T cells’ cell responses as efficiently as dendritic cells (57).

So called crosspresentation is at least 105 times less efficient than direct presentation and therefore is practically not achievable under physiological conditions (58).

If antigen accumulates in the endoplasmic (ER) reticulum because of transport problems, crosspresentation on to MHC class I can be demonstrated. This requires gigantic amounts of antigen accumulation in the ER, but this process has so far been difficult to quantitate in comparison to direct presentation (9).

Positive demonstration of crosspresentation in experiments is sometimes based on use of excessive amounts of protein antigen (e.g., OVA) and/or the use of unphysiological (i.e., much too sensitive) detection method, e.g., using very high frequencies of transgenic T cells (e.g., OVA-specific tgCD8+ T cells). In some experiments, virus inactivation is not controlled properly, permitting abortive (but not virus productive) infections that seemingly suggest crosspresentation instead of direct presentation [e.g., Ref. (8)].

An insulin-producing allogeneic cell graft strictly transplanted under the kidney capsule is accepted for more than >200 days by the host, but is promptly rejected if at the time of transplantation, or a few days later, the same cells are also given i.p. or i.v. (10) Once accepted, the allogeneic strictly peripheral cell graft is highly resistant to rejection by a transplanted corresponding allogeneic skin graft (or dendritic cells). This skin graft is rejected in a primary fashion, signaling absence of direct or indirect priming by the original allogeneic cell graft indicating absence of priming by the original cell graft. This prompt skin rejection does not cause rejection of the insulin-producing cell graft (10).

A strictly extralymphatic (7) tumor expressing a very strong and defined viral antigen (similar to insulin-producing self-beta-cells or allogeneic islet cells (1012) can grow successfully to become lethal tumors. This depends on the condition that at the time of syngeneic tumor cell transplantation no (or too few) tumor cells escape/or drain to secondary lymphatic organs (7). This potentially early direct immunization is distinct from the late process of metastasis to secondary lymphatic organs that very often represent immune escape of tumor cells (e.g., MHC mutants, mutations of the T cell epitope, barrier formation by fibrin, coagulation, etc.)

Discussion

DC transport antigen best to secondary lymphatic organs but only in an MHC class II associated fashion except of course if the DC is productively or abortively infected. The localization in or strictly outside of secondary lymphatic organs determines if and whether a CD8+ T cell immune response is induced or not. Crosspresentation of antigen to MHC class I by DC or macrophages is an experimental artifact due to overdosage or uncontrolled new cell internal synthesis. Pure crosspresentation is so inefficient, that it is largely impractical for application and therapeutic use against solid peripheral tumors.

References

1. Banchereau J, Steinman RM. Dendritic cells and the control of antigen immunity. Nature (1998) 392:245–52. doi:10.1038/32588

CrossRef Full Text

2. Ludewig B, Odermatt B, Landmann S, Hengartner H, Zinkernagel RM. Dendritic cells induce autoimmune diabetes and maintain disease via De novo formation of local lymphoid tissue. J Exp Med (1998) 188:1493–501. doi:10.1084/jem.188.8.1493

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

3. Ludewig B, Maloy KJ, Lopez-Macias C, Odermatt B, Hengartner H, Zinkernagel RM. Induction of optimal anti-viral neutralizing B cell responses by dendritic cells requires transport and release of virus particles in secondary lymphoid organs. Eur J Immunol (2000) 30:185–96. doi:10.1002/1521-4141(200001)30:1<185::AID-IMMU185>3.0.CO;2-L

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

4. Ludewig B, Ochsenbein AF, Odermatt B, Paulin D, Hengartner H, Zinkernagel RM. Immunotherapy with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease. J Exp Med (2000) 191:795–804. doi:10.1084/jem.191.5.795

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

5. Kündig TM, Bachmann MF, DiPaolo C, Simard JJ, Battegay M, Lother H, et al. Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science (1995) 268:1343–7. doi:10.1126/science.7761853

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

6. Zinkernagel RM. On cross-priming of MHC class I-specific CTL: rule or exception? Eur J Immunol (2002) 32:2385–92. doi:10.1002/1521-4141(200209)32:9<2385::AID-IMMU2385>3.0.CO;2-V

CrossRef Full Text

7. Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J, et al. Roles of tumour localization, second signals and cross priming in cytotoxic T cell induction. Nature (2001) 411:1058–64. doi:10.1038/35082583

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

8. Freigang S, Egger D, Bienz K, Hengartner H, Zinkernagel RM. Endogenous neosynthesis vs. cross-presentation of viral antigens for cytotoxic T cell priming. Proc Natl Acad Sci U S A (2003) 100:13477–82. doi:10.1073/pnas.1835685100

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

9. Freigang S, Eschli B, Harris N, Geuking M, Quirin K, Schrempf S, et al. A lymphocytic choriomeningitis virus glycoprotein variant that is retained in the endoplasmic reticulum efficiently cross-primes CD8(+) T cell responses. Proc Natl Acad Sci U S A (2007) 104:13426–31. doi:10.1073/pnas.0704423104

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

10. Pericin M, Althage A, Freigang S, Hengartner H, Rolland E, Dupraz P, et al. Allogeneic beta-islet cells correct diabetes and resist immune rejection. Proc Natl Acad Sci U S A (2002) 99:8203–6. doi:10.1073/pnas.122241299

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

11. Ohashi PS, Oehen S, Buerki K, Pircher HP, Ohashi CT, Odermatt B, et al. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell (1991) 65:305–17. doi:10.1016/0092-8674(91)90164-T

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

12. Ochsenbein AF, Klenerman P, Karrer U, Ludewig B, Pericin M, Hengartner H, et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci U S A (1999) 96:2233–8. doi:10.1073/pnas.96.5.2233

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: crosspresentation, fibroblast APCs, tumor immunity, tolerance, lymphnode

Citation: Zinkernagel RM (2014) On the role of dendritic cells versus other cells in inducing protective CD8+ T cell responses. Front. Immunol. 5:30. doi: 10.3389/fimmu.2014.00030

Received: 04 December 2013; Accepted: 19 January 2014;
Published online: 10 February 2014.

Edited by:

Kristian Michael Hargadon, Hampden-Sydney College, USA

Reviewed by:

Anne Hosmalin, Cochin Institute, France

Copyright: © 2014 Zinkernagel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: rolf.zinkernagel@usz.ch

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.