Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpα+ dendritic cells: a murine model.

Abstract

Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8α(-)Sirpα(+) cDCs, but not the major subset, CD8α(+)Sirpα(-) cDCs can selectively capture blood-borne antigens and crucially contribute to the self-tolerance. In the present study, we further demonstrated that Sirpα(+) cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirpα(+) cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirpα(+) cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpα(+) cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirpα(+) cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirpα(+) cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance.

• Authors: Tomohisa Baba, Mohamed El Sherif Badr, Utano Tomaru, Akihiro Ishizu, Naofumi Mukaida
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e41154 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22815949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation
• CCR2 protein, human
• CD11 Antigens
• Ccr2 protein, mouse
• Interleukin-2
• Ligands
• Ptpns1 protein, mouse
• Receptors, CCR2
• Receptors, Immunologic
• SIRPA protein, human
• Green Fluorescent Proteins

Topics

• Animals
• Antigens, Differentiation (biosynthesis)
• CD11 Antigens (biosynthesis)
• CD8-Positive T-Lymphocytes (cytology)
• Dendritic Cells (metabolism)
• Gene Deletion
• Green Fluorescent Proteins (metabolism)
• Humans
• Immune Tolerance
• Interleukin-2 (metabolism)
• Ligands
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Microscopy, Fluorescence (methods)
• Protein Binding
• Receptors, CCR2 (metabolism)
• Receptors, Immunologic (biosynthesis)
• Thymocytes (cytology)