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.

Ag and IL‐2 immune complexes efficiently expand Ag‐specific Treg cells that migrate in response to chemokines and reduce localized immune responses

“…We previously demonstrated that thymic CD11c + CD11b + CD8 − Sirpα + conventional DCs are principally located in interlobular vascular‐rich region of the thymic cortex and capture Ags from bloodstream to induce Ag‐specific Treg‐cell generation . Also under the present conditions, we observed that Ag‐specific Treg cells appeared in the circulation after their transient intrathymic expansion.…”

Thymic CCL2 influences induction of T-cell tolerance

“…Habeida et al showed that pDC could take up antigen in periphery and migrate to the thymus where they participated in T-cell tolerance induction [24]. The chemokine receptor involved in pDC migration was CCR9, and other studies have shown recruitment of DC via the CCL2 receptor CCR2 [23,53]. Development of pDC from intrathymic lymphoid precursors also cannot be excluded.…”

“…As expected, we confirmed CCR2 expression in the 3 DC subtypes [19] but we did not see any significant differences in CCR2 expression between pDC and Sirpa þ DC. Although expression of CCR2 message does not necessarily predict that cells will respond to CCL2, thymic DC recruitment via CCR2 has been described [23,53]. CCL2 binds to a number of receptors [55,56] including some with regulatory effect, so differential receptor expression profile by DC subsets might explain these observations.…”

Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)

“…The same report showed that migratory cDCs can accumulate in the cortex in the vicinity of small vessels and inside perivascular regions, whereas other investigators found that SIRPα + cDCs preferentially localized near blood vessels at the cortico-medullary junction and within deeper regions of the medulla (D. Atibalentja and E. Unanue, personal communication). Notwithstanding these apparent discrepancies, there is some consensus that SIRPα + migratory cDCs more efficiently sample intravenously injected model antigens from the bloodstream in vivo when compared with resident cDCs 35, 60-62 .…”