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Follicular regulatory T cells control humoral immune responses, but how these cells are in turn controlled has been unclear. Sharpe and colleagues demonstrate that signaling via PD-1 regulates number and function of these cells. CD4 + CXCR5 + Foxp3 + follicular regulatory T cells (T FR cells) inhibit humoral immunity mediated by CD4 + CXCR5 + Foxp3 − follicular helper T cells (T FH cells). Although the inhibitory receptor PD-1 is expressed by both cell types, its role in the differentiation of T FR cells is unknown. Here we found that mice deficient in PD-1 and its ligand PD-L1 had a greater abundance of T FR cells in the lymph nodes and that those T FR cells had enhanced suppressive ability. We also found substantial populations of T FR cells in mouse blood and demonstrated that T FR cells in the blood homed to lymph nodes and potently inhibited T FH cells in vivo . T FR cells in the blood required signaling via the costimulatory receptors CD28 and ICOS but were inhibited by PD-1 and PD-L1. Our findings demonstrate mechanisms by which the PD-1 pathway regulates antibody production and help reconcile inconsistencies surrounding the role of this pathway in humoral immunity.

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.

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 1 . 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 2 , 3 , this humoral response has not been shown to be pathogenic 3 , 4 . 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.

Priming of T cell responses involves the capture of antigen by immature dendritic cells (DCs) followed by a maturation process involving antigen processing, migration to secondary lymphoid tissue, induction of proinflammatory cytokines and costimulatory molecules and transport of peptide-MHC complexes to the cell surface. Certain members of the toll-like receptor (TLR) family and the tumor necrosis factor (TNF) receptor family transduce signals for DC maturation. However, additional receptors may also regulate DC maturation, reflecting the complexity of signals that participate in the initiation of adaptive immunity. We show here that immature human myeloid and plasmacytoid DCs express the B7 family member, B7-DC. B7-DC predominantly serves a stimulatory rather than inhibitory function in the human system. Along with CD3, it costimulates naïve and resting T cells to proliferate and produce proinflammatory cytokines. Moreover, it works in concert with B7-1 in its ability to activate the adaptive arm of the immune response. We also show that B7-DC expressed on the surface of an antigen presenting cell has a broader role than as a T cell costimulatory molecule. Cross-linking of B7-DC on immature myeloid DCs by plate-bound anti-B7-DC antibodies induces multiple features of DC maturation including activation of NF-κB and MAP kinase signaling, resulting in enhanced capacity to present antigen and activate T cells. DCs stimulated through B7-DC produce proinflammatory cytokines, induce T cell transmigration, and stimulate proliferation and activation of allogeneic and antigen specific T cell responses. Moreover, anti-B7-DC activated DCs down-regulate their phagocytic ability, as is the case during DC maturation, but interestingly have an initial enhancement of phagocytosis early in their maturation process. Cross-linking of B7-DC on plasmacytoid DCs induces type I interferon release at levels comparable to that induced by viral infection. These results suggest that, in addition to its role as a T cell costimulatory molecule, B7-DC serves a second role as a conduit for dendritic cell maturation.

Stress response obligates increased mitochondrial activities to meet stress induced high energy requirement. This stress mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress mitochondrial response paradigm to study the process in humans. We used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress induced cf mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS), as well as high resolution brain imaging based cortical thickness focusing on the mPFC. We found that salivary cf mtDNA was significant elevated immediately after the stress challenge (p=2.0x10-7) and gradually declined after. Exploratory causal analysis showed that this cf mtDNA response was not primarily driven by cortisol response. Instead, individuals with higher baseline dACC lactate+ levels, thought to in part reflect mitochondrial dysfunctions, was significantly associated with the cf mtDNA response (r=0.80, p<0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r=-0.52, p=0.01). Age had a U-shape effect such that cf mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct mtDNA response variance (p=0.003). This stress challenge-salivary cf mtDNA assay paradigm may offer a new, noninvasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.