Marginal zone CD169⁺macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance

Abstract

Tolerance to apoptotic cells is essential to prevent inflammatory pathology. Though innate responses are critical for immune suppression, our understanding of early innate immunity driven by apoptosis is lacking. Herein we report apoptotic cells induce expression of the chemokine CCL22 in splenic metallophillic macrophages, which is critical for tolerance. Systemic challenge with apoptotic cells induced rapid production of CCL22 in CD169 + (metallophillic) macrophages, resulting in accumulation and activation of FoxP3 + Tregs and CD11c + dendritic cells, an effect that could be inhibited by antagonizing CCL22-driven chemotaxis. This mechanism was essential for suppression after apoptotic cell challenge, because neutralizing CCL22 or its receptor, reducing Treg numbers, or blocking effector mechanisms abrogated splenic TGF-β and IL-10 induction; this promoted a shift to proinflammatory cytokines associated with a failure to suppress T cells. Similarly, CCR4 inhibition blocked long-term, apoptotic cell-induced tolerance to allografts. Finally, CCR4 inhibition resulted in a systemic breakdown of tolerance to self after apoptotic cell injection with rapid increases in anti-dsDNA IgG and immune complex deposition. Thus, the data demonstrate CCL22-dependent chemotaxis is a key early innate response required for apoptotic cell-induced suppression, implicating a previously unknown mechanism of macrophage-dependent coordination of early events leading to stable tolerance.transplantation | autoimmunity | migration | spleen | regulation

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity

“…Given that GCN2 fl LysM cre mice showed abrogated suppression of inflammatory immunity to apoptotic cells, we reasoned that long-term tolerance would be compromised as well. To test this, we used a model of female recognition to male H-Y antigen, in which exposure to male apoptotic cells leads to long-term tolerance to male skin grafts (7,16). In agreement with our previous studies, control groups of female mice rejected male skin, with a mean graft survival time of 26 d; in contrast, female mice receiving a single injection of male apoptotic cells before skin engraftment showed tolerance with no graft rejection (Fig.…”

“…We previously reported that apoptotic cell-associated antigens fail to induce adaptive T-cell responses (4,6,7). This effect is dependent on IDO1 expression and MZ MΦs, given that Ido1 −/− mice or mice depleted of MZ MΦs showed vigorous T-cell responses to apoptotic cells (6).…”

“…Systemic apoptotic cell exposure results in long-term tolerance to associated antigens and allografts (7). Given that GCN2 fl LysM cre mice showed abrogated suppression of inflammatory immunity to apoptotic cells, we reasoned that long-term tolerance would be compromised as well.…”

“…Macrophages (MΦ) are key drivers of the early innate response to apoptotic cells (4,5), and recent work has shown that tissue-resident MΦs are responsible for initial IL-10 production, promoting regulatory adaptive immunity to apoptotic cell antigens and prevention of inflammatory autoimmunity (4,6,7).…”

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

“…3 Moreover, recognition and engulfment of AC by macrophages and DC serves to sustain immune tolerance to self-antigens by virtue of the anti-inflammatory cytokines IL-10 and TGF-β released from these cells, and the recruitment of natural regulatory T cells. [4][5][6][7] Post AC engulfment, macrophages appear to be capable of fully digesting AC-associated antigens and limit their access to antigen presentation compartments, and therefore are inefficient at T-cell priming. 8 In contrast, DC are highly efficient at processing and presentation of engulfed antigens, using either direct or cross-presentation pathways, which either anergizes or activates potentially self-reactive T cells, depending on the context of antigen presentation.…”