In This Issue

doi:10.4049/jimmunol.1390047

Optical Disease Impacts Pregnancy

Neuromyelitis optica (NMO) is an inflammatory condition characterized by demyelination of the optic nerve and CNS. Abs directed against aquaporin-4, an astrocytic water channel protein, termed NMO-IgG, act with complement to cause astrocyte damage, neutrophil infiltration, and demyelination. As miscarriages occur more frequently in women with NMO, Saadoun et al. (p. 2999) investigated whether NMO-IgG was responsible for causing placental damage. In mice and humans, aquaporin-4 was expressed in the placental syncytiotrophoblast during midgestation and then decreased throughout pregnancy. Coadministration of NMO-IgG and complement to wild type mice caused both inflammatory cell infiltration into the placenta and placental necrosis. Other sites of aquaporin-4 expression, such as the brain, spinal cord, kidney, and skeletal muscle, were unaffected. Controls, including the absence of complement and non–NMO-IgG administration, and the use of aquaporin-4 deficient mice confirmed that complement activation by NMO-IgG caused the pathology. Thus, the authors demonstrate that NMO-IgG is capable of causing miscarriage and fetal death, indicating that NMO is not just a disease of the optic nerve but also has reproductive implications.

Lard Legacy

Everyone has heard the expression “you are what you eat,” but new research implies that children may pay the price for parental food choices. Myles et al. (p. 3200) investigated whether individuals who ingested a Western diet fatty acid profile passed on an author-termed “lard legacy” to their offspring. Mice breeding pairs were fed either a Western fatty acid profile diet or standard low-fat diet and then pups were weaned onto a standard control diet to test gestational and lactation effects on the immune development of offspring. While the pups from Western diet breeding pairs did not show signs of obesity or diabetes, they fared worse when it came to infection, autoimmune incidence and potential severity, and allergic sensitization. Colon inflammation was increased in “Western” versus “low-fat” pups, as was the level of circulating LPS. The authors concluded that the immune dysfunction found in “Western” pups resulted from an altered gut microbiome, an inheritance from their parents that were fed a higher fat diet. Thus, what parents eat during gestation can alter immune function in their offspring, likely due to inherited microbiota, and lends evidence to a “lard legacy” effect in mammals.

Fishing for Ig Diversity

Sharks and skates are the earliest known vertebrates to possess adaptive immunity based on their ability to rearrange genes that produce IgM and IgW, an ortholog to bony fish IgD. Little is known about how the Igω gene clusters that encode IgW are organized and rearranged, evolutionarily relevant information for divining how IgD V(D)J recombination events occur in human B cells. Using PCR and Southern blot analyses on DNA from nurse shark BAC clones, Zhang et al. (p. 3410) characterized eight functional miniloci gene clusters that composed the nurse shark Igω H chain, seven of which exhibited varying linkage relationships. They found each genomic cluster comprised one VH, two D, and one JH segments flanked by canonical RSS sites and six to eight constant (C) domain exons. Igω C region diversity was generated by isotype switching to other Igω or Igμ C regions and by unusually extensive RNA processing events. Some gene clusters also contained two noncontiguous secretory exons and a C domain exon with tailpiece, which enabled these miniloci to produce at least six and usually eight secreted IgW isoforms when combined with different C regions. These data indicate that isotype switching and RNA processing of Igω may produce a previously underappreciated level of C region diversity in the B cell repertoire of cartilaginous fishes.

Tailoring TCR Tumor Therapy

Tcell receptor gene therapy is a promising cancer immunotherapy treatment option; however, the immunosuppressive tumor environment can induce T cells to produce TGF-β1, a cytokine that can limit the potency of engineered tumoricidal T cells. To combat this issue, Bendle et al. (p. 3232) dually modified T cells to express the SV40 epitope IV-specific TCR (SV40_IV-TCR) that targets the prostate tumor Ag, SV40 large T Ag, and the dominant negative (dn) TGF-β-RII, which blocks TGF-β signaling in T cells. Adoptive transfer of these cells into transgenic adenocarcinoma of mouse prostate (TRAMP) mice, which express SV40 large T Ag in a prostate-specific manner and develop prostate epithelial carcinoma, resulted in enhanced survival and complete and sustained tumor regression in 75% of mice. TRAMP mice that received T cells transduced with the SV40_IV-TCR alone exhibited limited signs of both regression and enhanced survival. Remarkably, treatment of TRAMP mice with cotransduced T cells also restored prostate epithelium differentiation, indicating recovery of normal prostate gland function. Together, these data demonstrate that more extensive tailoring of TCR gene therapy can increase the efficacy of tumoricidal T cells in immunosuppressive tumor environments.

MicroRNA-210 Balances B Cell Immunity

MicroRNA-210 (miR-210) is widely expressed in hematopoietic stem cells, myeloid cells, and lymphocytes, but whether miR-210 contributes to lymphocyte development and function is unknown. In this issue, Mok et al. (p. 3037) used miR-210 knockout and transgenic (tg) models to delineate the effects of miR-210 deficiency or overexpression on B cell lineage commitment and activation. Five-month-old miR-210^−/− mice exhibited increased anti-dsDNA and anti-chromatin Abs and higher germinal center B cell numbers, but B cell development and responses to T-dependent and -independent Ags were largely unaltered. In contrast, B cell–specific overexpression of miR-210 in mice resulted in reduced numbers of pro-, pre-, and mature B cells in the bone marrow, a 20-fold expansion in the splenic B1a B cell compartment, reduced marginal zone B cell numbers, and impaired production of class-switched Abs compared with wild type controls. B2 cells from miR-210 tg mice were present in normal frequency but had reduced proliferative and cell-cycling capacities. Mechanistically, miR-210 induction in B cells was controlled by Oct-2, a transcription factor that mediates B cell activation. These results suggest that miR-210 fine-tunes B cell responses and helps strike a balance between immunity to pathogens versus self-reactivity.

Modeling Bacteria with Beads

Gram-positive bacteria exhibit structural complexities and a variety of covalent and noncovalent associations among the polysaccharide (PS) capsule, subcapsular proteins, and cell wall that complicate demarcating the contributions of each of these components to an effective Ab response. Colino et al. (p. 3254) delineated the immunogenic effects of covalent versus noncovalent associations between streptococcal type 14 capsular PS (PPS14) and bacterial protein pneumococcal surface protein A (PspA) in Ab responses by immunizing mice with bacteria-sized latex beads coated with PPS14 and pneumococcal surface protein A (PspA), which were either covalently linked (PPS14-PspA) or not (PPS14 + [PspA]). They found that priming and boosting with either type of coated bead resulted in robust secondary PPS14- and PspA-specific Ig responses that were dependent upon T cell help and ICOS costimulation. Similar to Ab responses to intact bacteria, Abs generated by PPS14 + [PspA] or PPS14-PspA bead immunization were enriched for the protective 44.1 Id, indicating that covalently-associated bacterial components are not required to elicit an effective Ab response. B cells from PPS14 + [PspA] bead-immunized mice or mice immunized with intact bacteria exhibited little affinity maturation compared with B cells from PPS14-PspA bead-immunized mice or mice primed and boosted with soluble PPS14-PspA. These data suggest that noncovalent associations between PS and PspA on latex particles recapitulate protective Ab responses to intact bacteria and that Ag-coated latex beads can serve as a viable vaccination platform.

Autoreactive and Anti-HIV?

Generating a vaccine that elicits broadly neutralizing Abs (bNAbs) is a common goal in current HIV vaccine research. Thus, determining how individual anti-HIV Abs are generated is critically important. In this issue, Doyle-Cooper et al. (p. 3186) characterize the human bNAb 4E10, while a companion study by Ota et al. (p. 3179) describes the function of b12, another anti-HIV bNAb. Using “knock-in” 4E10HL mice engineered to express the bNAb 4E10, which recognizes the membrane proximal region of HIV gp41, Doyle-Cooper et al. found that the B cells in these mice underwent significant negative selection, implying that 4E10 recognizes self-Ags. Receptor editing, clonal deletion, and receptor downregulation were all mechanisms of negative selection in 4E10HL mice. Negative selection was nearly complete, as only small amounts of serum IgM and IgG anti-gp41 were detectable in wild-type but not in RAG-1^−/− 4E10HL mice. Speculation into how the original 4E10 Ab could be generated in the face of strong negative selection led the authors to conclude that this Ab may have arisen in an HIV-infected individual resistant to developing AIDS but with a propensity for autoimmunity. Thus, the authors have established the importance of understanding the autoreactive potential of individual bNAbs for evaluating the safety and efficacy of possible vaccines.

DNA Methylation Maps CD8 T Cell Fate

The epigenetic processes (namely DNA methylation and histone modifications) that occur in CD8⁺ T cells during an acute immune response are largely unexplored. To shed light on the epigenetic mechanisms that program CD8⁺ effector T cell generation, Scharer et al. (p. 3419), used methyl-DNA immunoprecipitation and bisulfate sequencing to compare the genome-wide DNA methylomes of lymphocytic choriomeningitis virus (LCMV)-specific naive CD8⁺ T cells with methylomes of effector CD8⁺ T cells from mice eight days after acute LCMV infection. They found that DNA methylation was inversely correlated with expression of effector genes on a global scale. In effector CD8⁺ T cells, gene promoter regions involved in effector functions, such as Gzmb and Zbtb32 promoter regions, were more likely to be demethylated, whereas promoters from genes involved in CD8⁺ T cell development exhibited increased methylation. Differentially methylated regions occurred more frequently in promoter locations that contained transcription factor motifs associated with CD8⁺ effector T cell development, differentiation, and function. Together, these data suggest that DNA methylation is a dynamic epigenetic regulatory mechanism that modulates the formation and maintenance of CD8⁺ effector T cells during immune responses.