Experience

Publications

• Complement modulation of T cell immune responses during homeostasis and disease

  Journal of Leukocyte Biology

  The complement system is an ancient and critical effector mechanism of the innate immune system as it senses, kills, and clears infectious and/or dangerous particles and alerts the immune system to the presence of the infection and/or danger. Interestingly, an increasing number of reports have demonstrated a clear role for complement in the adaptive immune system as well. Of note, a number of recent studies have identified previously unknown roles for complement proteins, receptors, and regulators in T cell function. Here, we will review recent data demonstrating the influence of complement proteins C1q, C3b/iC3b, C3a (and C3aR), and C5a (and C5aR) and complement regulators DAF (CD55) and CD46 (MCP) on T cell function during homeostasis and disease. Although new concepts are beginning to emerge in the field of complement regulation of T cell function, future experiments should focus on whether complement is interacting directly with the T cell or is having an indirect effect on T cell function via APCs, the cytokine milieu, or downstream complement activation products. Importantly, the identification of the pivotal molecular pathways in the human systems will be beneficial in the translation of concepts derived from model systems to therapeutic targeting for treatment of human disorders.

• Complement modulation of T cell immune responses during homeostasis and disease

  Journal of Leukocyte Biology

  The complement system is an ancient and critical effector mechanism of the innate immune system as it senses, kills, and clears infectious and/or dangerous particles and alerts the immune system to the presence of the infection and/or danger. Interestingly, an increasing number of reports have demonstrated a clear role for complement in the adaptive immune system as well. Of note, a number of recent studies have identified previously unknown roles for complement proteins, receptors, and regulators in T cell function. Here, we will review recent data demonstrating the influence of complement proteins C1q, C3b/iC3b, C3a (and C3aR), and C5a (and C5aR) and complement regulators DAF (CD55) and CD46 (MCP) on T cell function during homeostasis and disease. Although new concepts are beginning to emerge in the field of complement regulation of T cell function, future experiments should focus on whether complement is interacting directly with the T cell or is having an indirect effect on T cell function via APCs, the cytokine milieu, or downstream complement activation products. Importantly, the identification of the pivotal molecular pathways in the human systems will be beneficial in the translation of concepts derived from model systems to therapeutic targeting for treatment of human disorders.

• Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation

  Journal of Leukocyte Biology

  A complete genetic deficiency of the complement protein C1q results in SLE with nearly 100% penetrance in humans, but the molecular mechanisms responsible for this association have not yet been fully determined. C1q opsonizes ACs for enhanced ingestion by phagocytes, such as Mϕ and iDCs, avoiding the extracellular release of inflammatory DAMPs upon loss of the membrane integrity of the dying cell. We previously showed that human monocyte-derived Mϕ and DCs ingesting autologous, C1q-bound LALs (C1q-polarized Mϕ and C1q-polarized DCs), enhance the production of anti-inflammatory cytokines, and reduce proinflammatory cytokines relative to Mϕ or DC ingesting LAL alone. Here, we show that C1q-polarized Mϕ have elevated PD-L1 and PD-L2 and suppressed surface CD40, and C1q-polarized DCs have higher surface PD-L2 and less CD86 relative to Mϕ or DC ingesting LAL alone, respectively. In an MLR, C1q-polarized Mϕ reduced allogeneic and autologous Th17 and Th1 subset proliferation and demonstrated a trend toward increased Treg proliferation relative to Mϕ ingesting LAL alone. Moreover, relative to DC ingesting AC in the absence of C1q, C1q-polarized DCs decreased autologous Th17 and Th1 proliferation. These data demonstrate that a functional consequence of C1q-polarized Mϕ and DC is the regulation of Teff activation, thereby “sculpting” the adaptive immune system to avoid autoimmunity, while clearing dying cells. It is noteworthy that these studies identify novel target pathways for therapeutic intervention in SLE and other autoimmune diseases.

• Complement modulation of T cell immune responses during homeostasis and disease

  Journal of Leukocyte Biology

  The complement system is an ancient and critical effector mechanism of the innate immune system as it senses, kills, and clears infectious and/or dangerous particles and alerts the immune system to the presence of the infection and/or danger. Interestingly, an increasing number of reports have demonstrated a clear role for complement in the adaptive immune system as well. Of note, a number of recent studies have identified previously unknown roles for complement proteins, receptors, and regulators in T cell function. Here, we will review recent data demonstrating the influence of complement proteins C1q, C3b/iC3b, C3a (and C3aR), and C5a (and C5aR) and complement regulators DAF (CD55) and CD46 (MCP) on T cell function during homeostasis and disease. Although new concepts are beginning to emerge in the field of complement regulation of T cell function, future experiments should focus on whether complement is interacting directly with the T cell or is having an indirect effect on T cell function via APCs, the cytokine milieu, or downstream complement activation products. Importantly, the identification of the pivotal molecular pathways in the human systems will be beneficial in the translation of concepts derived from model systems to therapeutic targeting for treatment of human disorders.

• Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation

  Journal of Leukocyte Biology

  A complete genetic deficiency of the complement protein C1q results in SLE with nearly 100% penetrance in humans, but the molecular mechanisms responsible for this association have not yet been fully determined. C1q opsonizes ACs for enhanced ingestion by phagocytes, such as Mϕ and iDCs, avoiding the extracellular release of inflammatory DAMPs upon loss of the membrane integrity of the dying cell. We previously showed that human monocyte-derived Mϕ and DCs ingesting autologous, C1q-bound LALs (C1q-polarized Mϕ and C1q-polarized DCs), enhance the production of anti-inflammatory cytokines, and reduce proinflammatory cytokines relative to Mϕ or DC ingesting LAL alone. Here, we show that C1q-polarized Mϕ have elevated PD-L1 and PD-L2 and suppressed surface CD40, and C1q-polarized DCs have higher surface PD-L2 and less CD86 relative to Mϕ or DC ingesting LAL alone, respectively. In an MLR, C1q-polarized Mϕ reduced allogeneic and autologous Th17 and Th1 subset proliferation and demonstrated a trend toward increased Treg proliferation relative to Mϕ ingesting LAL alone. Moreover, relative to DC ingesting AC in the absence of C1q, C1q-polarized DCs decreased autologous Th17 and Th1 proliferation. These data demonstrate that a functional consequence of C1q-polarized Mϕ and DC is the regulation of Teff activation, thereby “sculpting” the adaptive immune system to avoid autoimmunity, while clearing dying cells. It is noteworthy that these studies identify novel target pathways for therapeutic intervention in SLE and other autoimmune diseases.

• . Prevention of C5aR1 Signaling Delays Microglial Inflammatory Polarization, Favors Clearance Pathways and Suppresses Cognitive Loss

  J. Neuroinflammation

  Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, was previously shown to suppress pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, microglia were isolated from adult brain at multiple ages was compared across all genotypes from adult brain at 2, 5, 7 and 10 months of age followed by RNA-seq analysis. A lack of C5aR1 prevented behavior deficits at 10 months, although amyloid plaque load was not altered. Transcriptome analysis via RNA-seq identified inflammation related genes as differentially expressed, with increased expression in the Arctic mice relative to wild type and decreased expression in the Arctic/C5aR1KO relative to Arctic. In addition, phagosomal-lysosomal gene expression was increased in the Arctic mice relative to wild type but further increased in the Arctic/C5aR1KO mice. A decrease in neuronal complexity was seen in hippocampus of 10 month old Arctic mice at the time that correlates with the behavior deficit, both of which were rescued in the Arctic/C5aR1KO. CONCLUSIONS: These data are consistent with microglial polarization in the absence of C5aR1 signaling reflecting decreased induction of inflammatory genes and enhancement of degradation/clearance pathways, which is accompanied by preservation of CA1 neuronal complexity and hippocampal dependent cognitive function. The results provide links between microglial responses and loss of cognitive performance and, combined with the previous pharmacological approach to inhibit C5aR1 signaling, support the potential of this receptor as a novel therapeutic target for AD in humans.