SummaryRegulatory T cells (Tregs) and the PD-1: PD-ligand (PD-L) pathway are both critical to terminating immune responses. Elimination of either can result in the breakdown of tolerance and the development of autoimmunity. The PD-1: PD-L pathway can thwart self-reactive T cells and protect against autoimmunity in many ways. In this review, we highlight how PD-1 and its ligands defend against potentially pathogenic self-reactive effector T cells by simultaneously harnessing two mechanisms of peripheral tolerance: (i) the promotion of Treg development and function and (ii) the direct inhibition of potentially pathogenic self-reactive T cells that have escaped into the periphery. Treg cells induced by the PD-1 pathway may also assist in maintaining immune homeostasis, keeping the threshold for T-cell activation high enough to safeguard against autoimmunity. PD-L1 expression on non-hematopoietic cells as well as hematopoietic cells endows PD-L1 with the capacity to promote Treg development and enhance Treg function in lymphoid organs and tissues that are targets of autoimmune attack. At sites where transforming growth factor-β is present (e.g. sites of immune privilege or inflammation), PD-L1 may promote the de novo generation of Tregs. When considering the consequences of uncontrolled immunity, it would be therapeutically advantageous to manipulate Treg development and sustain Treg function. Thus, this review also discusses how the PD-1 pathway regulates a number of autoimmune diseases and the therapeutic potential of PD-1: PD-L modulation.

Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1−/− antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1–coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1−/−PD-L2−/− Rag−/− recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.

SummaryDendritic cells, but not macrophages, efficiently phagocytose apoptotic cells and cross-present viral, tumor, and self-antigens to CD8 ϩ T cells. This in vitro pathway corresponds to the in vivo phenomena of cross-priming and cross-tolerance. Here, we demonstrate that phagocytosis of apoptotic cells is restricted to the immature stage of dendritic cell (DC) development, and that this process is accompanied by the expression of a unique profile of receptors, in particular the ␣ v ␤ 5 integrin and CD36. Upon maturation, these receptors and, in turn, the phagocytic capacity of DCs, are downmodulated. Macrophages engulf apoptotic cells more efficiently than DCs, and although they express many receptors that mediate this uptake, they lack the ␣ v ␤ 5 integrin. Furthermore, in contrast to DCs, macrophages fail to cross-present antigenic material contained within the engulfed apoptotic cells. Thus, DCs use unique pathways for the phagocytosis, processing, and presentation of antigen derived from apoptotic cells on class I major histocompatibility complex. We suggest that the ␣ v ␤ 5 integrin plays a critical role in the trafficking of exogenous antigen by immature DCs in this cross-priming pathway.

Newly defined CD4+CXCR5+FoxP3+ T Follicular Regulatory (TFR) cells inhibit CD4+CXCR5+FoxP3− T Follicular Helper (TFH)-mediated humoral immunity. Although PD-1 is expressed by both cell types, the role of this inhibitory receptor on TFR differentiation is unknown. Here we show that PD-1/PD-L1 deficient mice have increased lymph node TFR cells, which have enhanced suppressive capacity. We also find substantial populations of TFR cells in mouse blood, and demonstrate that blood TFR cells home to lymph nodes and potently inhibit TFH cells in vivo. Blood TFR cells require CD28 and ICOS signaling, but are inhibited by PD-1/PD-L1. These findings reveal novel mechanisms by which the PD-1 pathway regulates antibody production and helps to reconcile inconsistencies surrounding the role of this pathway in humoral immunity.

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Naturally occurring CD4+ TR cells that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis preventing immune pathological responses to self and foreign antigens. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for TR in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in TR function. Using a colitis transfer model, we previously showed that anti-CTLA-4 mAb treatment abrogates suppression of colitis mediated by CD4+ CD25+ TR. Here we demonstrate that anti-CTLA-4 mAb treatment inhibits TR function via direct effects on CTLA-4 expressing TR cells, and not via hyper-activation of colitogenic T cells. Although anti-CTLA-4 mAb treatment completely inhibits TR function, it does not affect TR cell expansion, persistence or homing to the gut-associated lymphoid tissue, indicative of the blockade of a signal required for TR cell activity. In contrast to the striking effect of the antibody, CTLA-4 deficient mice can produce functional TR cells, suggesting that compensatory mechanisms can develop. This study provides direct evidence that CTLA-4 has a specific, non-redundant role in the function of normal regulatory T cells. This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break TR-mediated self-tolerance.

Models for immune-mediated tumor regression in mice have defined an essential role for cytotoxic T lymphocytes (CTLs); however, naturally occurring tumor immunity in humans is poorly understood. Patients with paraneoplastic cerebellar degeneration (PCD) provide an opportunity to explore the mechanisms underlying tumor immunity to breast and ovarian cancer. Although tumor immunity and autoimmune neuronal degeneration in PCD correlates with a specific antibody response to the tumor and brain antigen cdr2, this humoral response has not been shown to be pathogenic. Here we present evidence for a specific cellular immune response in PCD patients. We have detected expanded populations of MHC class I-restricted cdr2-specific CTLs in the blood of 3/3 HLA-A2.1+ PCD patients, providing the first description, to our knowledge, of tumor-specific CTLs using primary human cells in a simple recall assay. Cross-presentation of apoptotic cells by dendritic cells also led to a potent CTL response. These results indicate a model whereby immature dendritic cells that engulf apoptotic tumor cells can mature and migrate to draining lymph organs where they could induce a CTL response to tissue-restricted antigens. In PCD, peripheral activation of cdr2-specific CTLs is likely to contribute to the subsequent development of the autoimmune neuronal degeneration.