Copy Number Variation of CCL3-like Genes Affects Rate of Progression to Simian-AIDS in Rhesus Macaques (Macaca mulatta)

Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (p<0.001) with lower CCL3L copy number associating with more rapid disease course. We also find that CCL3L copy number varies significantly (p<10−6) among rhesus subpopulations, with Indian-origin macaques having, on average, half as many CCL3L gene copies as Chinese-origin macaques. Lastly, we confirm that CCL3L shows variable copy number in humans and chimpanzees and report on CCL3L CNV within and among three additional primate species. On the basis of our findings we suggest that (1) the difference in population level copy number may explain previously reported observations of longer post-infection survivorship of Chinese-origin rhesus macaques, (2) stratification by CCL3L copy number in rhesus SIV vaccine trials will increase power and reduce noise due to non-vaccine-related differences in survival, and (3) CCL3L CNV is an ancestral component of the primate immune response and, therefore, copy number variation has not been driven by HIV or SIV per se

The atypical chemokine receptor ACKR2 suppresses Th17 responses to protein autoantigens

Chemokine-directed leukocyte migration is a critical component of all innate and adaptive immune responses. The atypical chemokine receptor ACKR2 is expressed by lymphatic endothelial cells and scavenges pro-inflammatory CC chemokines to indirectly subdue leukocyte migration. This contributes to the resolution of acute inflammatory responses &lt;i&gt;in vivo&lt;/i&gt;. ACKR2 is also universally expressed by innate-like B cells, suppressing their responsiveness to the non-ACKR2 ligand CXCL13, and controlling their distribution &lt;i&gt;in vivo&lt;/i&gt;. The role of ACKR2 in autoimmunity remains relatively unexplored, although &lt;i&gt;Ackr2&lt;/i&gt; deficiency reportedly lessens the clinical symptoms of experimental autoimmune encephalomyelitis induced by immunization with encephalogenic peptide (MOG&lt;sub&gt;35–55&lt;/sub&gt;). This was attributed to poor T-cell priming stemming from the defective departure of dendritic cells from the site of immunization. However, we report here that &lt;i&gt;Ackr2&lt;/i&gt;-deficient mice, on two separate genetic backgrounds, are not less susceptible to autoimmunity induced by immunization, and in some cases develop enhanced clinical symptoms. Moreover, ACKR2 deficiency does not suppress T-cell priming in response to encephalogenic peptide (MOG&lt;sub&gt;35–55&lt;/sub&gt;), and responses to protein antigen (collagen or MOG&lt;sub&gt;1–125&lt;/sub&gt;) are characterized by elevated interleukin-17 production. Interestingly, after immunization with protein, but not peptide, antigen, &lt;i&gt;Ackr2&lt;/i&gt; deficiency was also associated with an increase in lymph node B cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that enhances T helper type 17 (Th17) cell development and survival. Thus, &lt;i&gt;Ackr2&lt;/i&gt; deficiency does not suppress autoreactive T-cell priming and autoimmune pathology, but can enhance T-cell polarization toward Th17 cells and increase the abundance of GM-CSF&lt;sup&gt;+&lt;/sup&gt; B cells in lymph nodes draining the site of immunization

The atypical chemokine receptor ACKR2 suppresses Th17 responses to protein autoantigens

Chemokine-directed leukocyte migration is a critical component of all innate and adaptive immune responses. The atypical chemokine receptor ACKR2 is expressed by lymphatic endothelial cells and scavenges pro-inflammatory CC chemokines to indirectly subdue leukocyte migration. This contributes to the resolution of acute inflammatory responses &lt;i&gt;in vivo&lt;/i&gt;. ACKR2 is also universally expressed by innate-like B cells, suppressing their responsiveness to the non-ACKR2 ligand CXCL13, and controlling their distribution &lt;i&gt;in vivo&lt;/i&gt;. The role of ACKR2 in autoimmunity remains relatively unexplored, although &lt;i&gt;Ackr2&lt;/i&gt; deficiency reportedly lessens the clinical symptoms of experimental autoimmune encephalomyelitis induced by immunization with encephalogenic peptide (MOG&lt;sub&gt;35–55&lt;/sub&gt;). This was attributed to poor T-cell priming stemming from the defective departure of dendritic cells from the site of immunization. However, we report here that &lt;i&gt;Ackr2&lt;/i&gt;-deficient mice, on two separate genetic backgrounds, are not less susceptible to autoimmunity induced by immunization, and in some cases develop enhanced clinical symptoms. Moreover, ACKR2 deficiency does not suppress T-cell priming in response to encephalogenic peptide (MOG&lt;sub&gt;35–55&lt;/sub&gt;), and responses to protein antigen (collagen or MOG&lt;sub&gt;1–125&lt;/sub&gt;) are characterized by elevated interleukin-17 production. Interestingly, after immunization with protein, but not peptide, antigen, &lt;i&gt;Ackr2&lt;/i&gt; deficiency was also associated with an increase in lymph node B cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that enhances T helper type 17 (Th17) cell development and survival. Thus, &lt;i&gt;Ackr2&lt;/i&gt; deficiency does not suppress autoreactive T-cell priming and autoimmune pathology, but can enhance T-cell polarization toward Th17 cells and increase the abundance of GM-CSF&lt;sup&gt;+&lt;/sup&gt; B cells in lymph nodes draining the site of immunization

Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures

International audienceImmune responses are regulated by effector cytokines and chemokines that signal through cell surface receptors. Mammalian decoy receptors — which are typically soluble or inactive versions of cell surface receptors or soluble protein modules termed binding proteins — modulate and antagonize signalling by canonical effector–receptor complexes. Viruses have developed a diverse array of molecular decoys to evade host immune responses; these include viral homologues of host cytokines, chemokines and chemokine receptors; variants of host receptors with new functions; and novel decoy receptors that do not have host counterparts. Over the past decade, the number of known mammalian and viral decoy receptors has increased considerably, yet a comprehensive curation of the corresponding structure–mechanism relationships has not been carried out. In this Review, we provide a comprehensive resource on this topic with a view to better understanding the roles and evolutionary relationships of mammalian and viral decoy receptors, and the opportunities for leveraging their therapeutic potential