Critical role of integrin CD11c in splenic dendritic cell capture of missing-self CD47 cells to induce adaptive immunity

Abstract

CD11c, also known as integrin alpha X, is the most widely used defining marker for dendritic cells (DCs). CD11c can bind complement iC3b and mediate phagocytosis in vitro, for which it is also referred to as complement receptor 4. However, the functions of this prominent marker protein in DCs, especially in vivo, remain poorly defined. Here, in the process of studying DC activation and immune responses induced by cells lacking self-CD47, we found that DC capture of CD47-deficient cells and DC activation was dependent on the integrin-signaling adaptor Talin1. Specifically, CD11c and its partner Itgb2 were required for DC capture of CD47-deficient cells. CD11b was not necessary for this process but could partially compensate in the absence of CD11c. Mice with DCs lacking Talin1, Itgb2, or CD11c were defective in supporting T-cell proliferation and differentiation induced by CD47-deficient cell associated antigen. These findings establish a critical role for CD11c in DC antigen uptake and activation in vivo. They may also contribute to understanding the functional mechanism of CD47-blockade therapies.

Structure and function of the immune system in the spleen

“…cDC2s recognize sheep RBCs as foreign through species differences in the “don’t eat me” signal CD47, an integrin-associated protein that binds SIRPα and inhibits phagocytosis (50). DC priming of Tfh cells after recognition of CD47-deficient sheep RBCs is dependent on the integrin-signaling adapter protein, Talin-1 (95). However, the mechanism by which cDC2s sense allogeneic RBCs as foreign remains unknown.…”

<p>A Hybrid Glioma Tumor Cell Lysate Immunotherapy Vaccine Demonstrates Good Clinical Efficacy in the Rat Model</p>

“…26 CD11c, a classical marker of mature DCs and a member of the β2-integrin family, can regulate the proliferation and function of CD4+ and CD8+ T cells. 27 – 30 The marker is highly expressed on the surface of most DCs, monocytes, and macrophages but is less abundant on the surface of plasmacytoid DCs. 31 However, high numbers of CD11c+ DCs suppress the immune system and reduce the antitumor ability.…”

Thymoproteasome-Expressing Mesenchymal Stromal Cells Confer Protective Anti-Tumor Immunity via Cross-Priming of Endogenous Dendritic Cells

“…The basal level of PIS on live MSC-TPr was substantially higher than that on Ctl MSCs and further enhanced after heat-killing ( Figure 6E ) along with a loss in H2-K b detection on the cell surface ( Figure 6F ). These observations served as impetus to compare the anti-tumor ability of heat-killed MSC-TPr (dead cells with high PIS cell surface levels but no chemokines) versus live MSC-TPr delivered to mice pre-treated with anti-CD11c antibodies as a means to functionally impair DC cross-priming ( 22 ). Both treatments impaired the anti-tumor efficacy of the vaccine ( Figure 6G ) clearly indicating that the fate of the immune response induced by MSC-TPr results from a delicate balance between efferocytosis mediated by a subset of CD11 hi phagocytes known for mediating immune-suppression, and DC cross-priming responsible for eliciting a pro-inflammatory response.…”

“…If phagocytes impair the anti-tumor response of the vaccine and MSC-TPr cannot behave as an antigen-presenting cell in vivo , then how can animals develop a protective OVA-specific CD8 T-cell response? The simplest explanation lies in endogenous DC cross-priming as animals undergoing anti-CD11c treatment are incapable of mounting protective anti-tumor responses ( 22 ). Besides, the loss of function observed with heat-killed MSC-TPr also indicate the need for metabolically-fit cells secreting specific chemokines and perhaps other soluble growth factor to recruit and cross-prime endogenous DCs.…”