Recognition Of Class Research Articles

Direct recognition of hepatocyte-expressed MHC class I alloantigens is required for tolerance induction.

Adeno-associated viral vector-mediated (AAV-mediated) expression of allogeneic major histocompatibility complex class I (MHC class I) in recipient liver induces donor-specific tolerance in mouse skin transplant models in which a class I allele (H-2Kb or H-2Kd) is mismatched between donor and recipient. Tolerance can be induced in mice primed by prior rejection of a donor-strain skin graft, as well as in naive recipients. Allogeneic MHC class I may be recognized by recipient T cells as an intact molecule (direct recognition) or may be processed and presented as an allogeneic peptide in the context of self-MHC (indirect recognition). The relative contributions of direct and indirect allorecognition to tolerance induction in this setting are unknown. Using hepatocyte-specific AAV vectors encoding WT allogeneic MHC class I molecules, or class I molecules containing a point mutation (D227K) that impedes direct recognition of intact allogeneic MHC class I by CD8+ T cells without hampering the presentation of processed peptides derived from allogeneic MHC class I, we show here that tolerance induction depends upon recognition of intact MHC class I. Indirect recognition alone yielded a modest prolongation of subsequent skin graft survival, attributable to the generation of CD4+ Tregs, but it was not sufficient to induce tolerance.

Abstract 5665: NOD-scid IL2rg null (NSG) mice deficient in murine MHC Class I and Class II expression support engraftment of functional human T cells in the absence of acute xenogeneic GVHD following injection of PBMC

Abstract The study of human immune system-tumor interactions has been limited historically by a paucity of models that fully reproduce human immune system function. Humanized mice are emerging as an exciting platform to study human immuno-oncology and provide preclinical tools to test cutting edge immunotherapies. An effective and simplistic approach to engraft immunodeficient mice with functional human T cells is the injection of human peripheral blood mononuclear cells (PBMC). This PBMC engraftment model (termed Hu-PBL-SCID mice) has supported studies of human infectious agents, allograft rejection, and human T cell immune function. The Hu-PBL-SCID model has also supported studies of human immune system-tumor interactions following injection of human PBMC into immunodeficient mice implanted with patient-derived (PDX) tumors. However, a major limitation of this model is the development of acute xenogeneic graft-versus-host disease (GVHD) due to human T cell recognition of murine MHC class I and class II. To address this limitation, we created two strains of NSG mice that lack murine MHC antigens, one by crossing NSG-B2Mnull with NSG-(IA IEnull) mice, the second by knocking out the MHC class II IAb gene in NSG-(Kb Db)null mice using TALEN technology. We observed that human IgG clearance was rapid in NSG-B2Mnull (IA IEnull) mice that lack functional FcRn activity whereas clearance in NSG-(Kb Db)null (IAnull) mice was comparable to that observed in NSG mice. Injection of human PBMC into both strains led to engraftment of human T cells that exhibited an approximate 3:1 CD4:CD8 ratio with long term engraftment and without development of acute GVHD. The engrafted human T cells were functional as documented by their ability to reject human islet allografts. Administration of human recombinant IL2 using AAV-IL2 to NSG-(Kb Db)null (IAnull) mice resulted in increased human CD45 cell engraftment, including heightened levels of human Tregs. However, high IL2 levels led to the development of acute GVHD. Moreover, NSG-(Kb Db)null (IAnull) mice injected with a PDX tumor and PBMC from an allogeneic donor supported significant tumor growth in the absence of acute GVHD. These data document that NSG mice deficient in murine MHC class I and class II can support studies of human immune system-tumor interactions in the absence of acute GVHD and provide a model for evaluation of human antibody therapeutics. Citation Format: Michael A. Brehm, Michael Wiles, Laurie Kenney, Ben Low, Roland M. Tisch, Lisa Burzenski, James G. Keck, Dale L. Greiner, Leonard D. Shultz. NOD-scid IL2rgnull (NSG) mice deficient in murine MHC Class I and Class II expression support engraftment of functional human T cells in the absence of acute xenogeneic GVHD following injection of PBMC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5665.

A Study on Recognition and Retirement Preparation of Subjective Social Class Using Data Matching

A Study on Recognition and Retirement Preparation of Subjective Social Class Using Data Matching

NOD-scid IL2rg null (NSG) mice deficient in murine MHC Class I and Class II expression support engraftment of functional human T cells in the absence of acute xenogeneic GVHD following injection of PBMC

Abstract Humanized mice are emerging as an exciting platform to study human immuno-oncology and provide preclinical tools to test cutting edge immunotherapies. An effective and simplistic approach to engraft immunodeficient mice with functional human T cells is the injection of human peripheral blood mononuclear cells (PBMC). This PBMC engraftment model (termed Hu-PBL-SCID) has supported studies of human immune system-tumor interactions following injection of human PBMC into immunodeficient mice implanted with patient-derived (PDX) tumors. However, a major limitation of this model is the development of acute xenogeneic GVHD due to human T cell recognition of murine MHC class I and class II. To address this limitation, we created two strains of NSG mice that lack murine MHC antigens, one by crossing NSG-B2Mnullwith NSG-(IA IEnull) mice, the second by knocking out the MHC class II IAb gene in NSG-(KbDb)null mice using TALEN technology. We observed that human IgG clearance was rapid in NSG-B2Mnull(IA IEnull) mice that lack functional FcRn activity whereas clearance in NSG-(KbDb)null(IAnull) mice was comparable to that observed in NSG mice. Injection of human PBMC into both strains led to long term engraftment of human T cells without development of acute GVHD. The engrafted human T cells were functional as documented by their ability to reject human islet allografts. Moreover, NSG-(KbDb)null(IAnull) mice injected with a PDX tumor and PBMC from an allogeneic donor supported significant tumor growth in the absence of acute GVHD. These data document that NSG mice deficient in murine MHC class I and class II support studies of human immune system-tumor interactions in the absence of acute GVHD and provide a model to evaluate human antibody therapeutics.

Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma.

T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who achieved a complete response following adoptive transfer of tumor-infiltrating lymphocytes (TILs). Tumor exome sequencing surprisingly revealed fewer than 30 nonsynonymous somatic mutations, including oncogenic BRAFV600E. Analysis of the specificity of TILs identified rare CD4+ T cells specific for BRAFV600E and diverse CD8+ T cells reactive to nonmutated self-antigens. These specificities increased in blood after TIL transfer and persisted long-term, suggesting they contributed to the effective antitumor immune response. Gene transfer of the BRAFV600E-specific T cell receptor (TCR) conferred recognition of class II MHC-positive cells expressing the BRAF mutation. Therapy with TCR-engineered BRAFV600E-specific CD4+ T cells may have direct antitumor effects and augment CD8+ T cell responses to self- and/or mutated tumor antigens in patients with BRAF-mutated cancers.

NKG2H-Expressing T Cells Negatively Regulate Immune Responses.

The biology and function of NKG2H receptor, unlike the better characterized members of the NKG2 family NKG2A, NKG2C, and NKG2D, remains largely unclear. Here, we show that NKG2H is able to associate with the signaling adapter molecules DAP12 and DAP10 suggesting that this receptor can signal for cell activation. Using a recently described NKG2H-specific monoclonal antibody (mAb), we have characterized the expression and function of lymphocytes that express this receptor. NKG2H is expressed at the cell surface of a small percentage of peripheral blood mononuclear cell (PBMC) and is found more frequently on T cells, rather than NK cells. Moreover, although NKG2H is likely to trigger activation, co-cross-linking of this receptor with an NKG2H-specific mAb led to decreased T cell activation and proliferation in polyclonal PBMC cultures stimulated by anti-CD3 mAbs. This negative regulatory activity was seen only after cross-linking with NKG2H, but not NKG2A- or NKG2C-specific monoclonal antibodies. The mechanism underlying this negative effect is as yet unclear, but did not depend on the release of soluble factors or recognition of MHC class I molecules. These observations raise the intriguing possibility that NKG2H may be a novel marker for T cells able to negatively regulate T cell responses.

Are donor lymphocytes a barrier to transplantation tolerance?

Following solid organ transplantation (SOT), populations of donor lymphocytes are frequently found in the recipient circulation. Their impact on host alloimmunity has long been debated but remains unclear, and it has been suggested that transferred donor lymphocytes may either promote tolerance to the graft or hasten its rejection. We discuss possible mechanisms by which the interaction of donor passenger lymphocytes with recipient immune cells may either augment the host alloimmune response or inhibit it. Recent work has highlighted that donor T lymphocytes are the most numerous of the donor leukocyte populations within a SOT and that these may be transferred to the recipient after transplantation. Surprisingly, graft-versus-host recognition of major histocompatibility complex class II on host B cells by transferred donor CD4 T cells can result in marked augmentation of host humoral alloimmunity and lead to early graft failure. Killing of donor CD4 T cells by host natural killer cells is critical in preventing this augmentation. The ability of passenger donor CD4 T cells to effect long-term augmentation of the host humoral alloimmune response raises the possibility that ex-vivo treatment or modification of the donor organ prior to implantation may improve long-term transplant outcomes.

Crystal structure of a TAPBPR-MHC I complex reveals the mechanism of peptide editing in antigen presentation.

Central to CD8+ T cell-mediated immunity is the recognition of peptide-major histocompatibility complex class I (p-MHC I) proteins displayed by antigen-presenting cells. Chaperone-mediated loading of high-affinity peptides onto MHC I is a key step in the MHC I antigen presentation pathway. However, the structure of MHC I with a chaperone that facilitates peptide loading has not been determined. We report the crystal structure of MHC I in complex with the peptide editor TAPBPR (TAP-binding protein-related), a tapasin homolog. TAPBPR remodels the peptide-binding groove of MHC I, resulting in the release of low-affinity peptide. Changes include groove relaxation, modifications of key binding pockets, and domain adjustments. This structure captures a peptide-receptive state of MHC I and provides insights into the mechanism of peptide editing by TAPBPR and, by analogy, tapasin.

The Relationship of Subjective Recognition of Social Class and Mental Health in Korean Adult

The Relationship of Subjective Recognition of Social Class and Mental Health in Korean Adult

Recognition of Intact Donor Class I by Recipient CD8+ T Cells is Required for Tolerance Induction Following Liver-Directed Transgene Expression

Introduction: AAV-mediated expression of donor MHC I (H-2Kb or H-2Kd) in recipient liver induces donor-specific tolerance in a mouse skin transplant model where Kb or Kd are mismatched between donor and host [1]. Recognition of both intact and processed allogeneic class I could contribute to tolerance induction. Aims and Methods: To determine the relative importance of intact and processed class I in tolerance induction, we generated rAAV-Kb-D227K and Kd-D227K vectors where a point mutation in the class I alpha 3 domain abrogates CD8 binding [2] and direct allorecognition but does not interfere with recognition of processed peptides. Expression of WT or mutant class I on hepatocytes was assessed by FACS and IHC. TCR-transgenic T cells recognizing intact (Des-RAG) or processed (TCR75) allogeneic class I were used as reporter cells in adoptive transfer experiments. Skin bearing the mismatched MHC I was grafted onto uninjected recipients or mice inoculated with rAAV encoding WT or D227K mutant Kb or Kd. In some recipients, Tregs were depleted using anti-FR4 or Diphtheria toxin (DT). Interferon gamma production by responding T cells was determined using ELISpot. Results: WT and D227K class I were expressed on hepatocytes at comparable levels. Adoptive transfer assays confirmed that the D227K mutation abrogated recognition of intact Kb by CD8+ Des-RAG T cells, whilst recognition of processed Kd peptides by TCR75-RAG cells was unimpaired. Uninjected B10.BR mice rejected Kb-mismatched 178.3 skin (MST = 16 d), while grafts onto rAAV-Kb-injected mice survived indefinitely (p < 0.001). rAAV-Kb-D227K only slightly prolonged graft survival (MST = 27d, p < 0.05). These results were recapitulated in the B6.Kd to C57BL/6 model. The modest survival prolongation of skin grafts in mice inoculated with Kb-D227K was abrogated when the recipients were treated with anti-FR4 (clone TH6) to deplete Tregs. Similarly, the survival prolongation of Kd-mismatched B6.Kd grafts onto DEREG recipients treated with rAAV-Kd-D227K (MST = 28d compared with 20d in mice receiving DT alone) was blocked when mice receiving Kd-D227K were also treated with DT (MST 18 days, p = 0.0046). Treg depletion did not shorten survival of skin grafts in mice inoculated with WT MHC class I vectors. Interferon-gamma production by unfractionated or CD8-enriched splenocytes from primed C57BL/6 mice in response to B6.Kd stimulators was over fourfold lower in mice inoculated with WT Kd than in those receiving Kd-D227K (p = 0.038). Conclusions: Recognition of intact MHC class I by alloreactive CD8+ T cells is required for tolerance induction via liver-directed expression of donor MHC class I. Indirect recognition of class I allopeptides and generation of Tregs can produce a modest prolongation of class I-mismatched skin graft survival but does not induce tolerance.FigureFigure

Chloroplast phylogenomic analyses reveal the deepest-branching lineage of the Chlorophyta, Palmophyllophyceae class. nov.

The green plants (Viridiplantae) are an ancient group of eukaryotes comprising two main clades: the Chlorophyta, which includes a wide diversity of green algae, and the Streptophyta, which consists of freshwater green algae and the land plants. The early-diverging lineages of the Viridiplantae comprise unicellular algae, and multicellularity has evolved independently in the two clades. Recent molecular data have revealed an unrecognized early-diverging lineage of green plants, the Palmophyllales, with a unique form of multicellularity, and typically found in deep water. The phylogenetic position of this enigmatic group, however, remained uncertain. Here we elucidate the evolutionary affinity of the Palmophyllales using chloroplast genomic, and nuclear rDNA data. Phylogenetic analyses firmly place the palmophyllalean Verdigellas peltata along with species of Prasinococcales (prasinophyte clade VI) in the deepest-branching clade of the Chlorophyta. The small, compact and intronless chloroplast genome (cpDNA) of V. peltata shows striking similarities in gene content and organization with the cpDNAs of Prasinococcales and the streptophyte Mesostigma viride, indicating that cpDNA architecture has been extremely well conserved in these deep-branching lineages of green plants. The phylogenetic distinctness of the Palmophyllales-Prasinococcales clade, characterized by unique ultrastructural features, warrants recognition of a new class of green plants, Palmophyllophyceae class. nov.

Tumor-infiltrating HLA-matched CD4+ T cells retargeted against Hodgkin and Reed–Sternberg cells

ABSTRACTHodgkin lymphoma (HL) presents with a unique histologic pattern. Pathognomonic Hodgkin and Reed–Sternberg (HRS) cells usually account for less than 1% of the tumor and are embedded in a reactive infiltrate mainly comprised of CD4+ T cells. HRS cells induce an immunosuppressive microenvironment and thereby escape antitumor immunity. To investigate the impact of interactions between HRS cells and T cells, we performed long-term co-culture studies that were further translated into a xenograft model. Surprisingly, we revealed a strong antitumor potential of allogeneic CD4+ T cells against HL cell lines. HRS and CD4+ T cells interact by adhesion complexes similar to immunological synapses. Tumor-cell killing was likely based on the recognition of allogeneic major histocompatibility complex class II (MHC-II) receptor, while CD4+ T cells from MHC-II compatible donors did not develop any antitumor potential in case of HL cell line L428. However, gene expression profiling (GEP) of co-cultured HRS cells as well as tumor infiltration of matched CD4+ T cells indicated cellular interactions. Moreover, matched CD4+ T cells could be activated to kill CD30+ HRS cells when redirected with a CD30-specific chimeric antigen receptor. Our work gives novel insights into the crosstalk between HRS and CD4+ T cells, suggesting the latter as potent effector cells in the adoptive cell therapy of HL.

Blocking MHC class II on human endothelium mitigates acute rejection.

Acute allograft rejection is mediated by host CD8+ cytotoxic T lymphocytes (CTL) targeting graft class I major histocompatibility complex (MHC) molecules. In experimental rodent models, rejection requires differentiation of naive CD8+ T cells into alloreactive CTL within secondary lymphoid organs, whereas in humans, CTL may alternatively develop within the graft from circulating CD8+ effector memory T cells (TEM) that recognize class I MHC molecules on graft endothelial cells (EC). This latter pathway is poorly understood. Here, we show that host CD4+ TEM, activated by EC class II MHC molecules, provide critical help for this process. First, blocking HLA-DR on EC lining human artery grafts in immunodeficient mice reduces CD8+ CTL development within and acute rejection of the artery by adoptively transferred allogeneic human lymphocytes. Second, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on EC prevents CD4+ TEM from helping CD8+ TEM to develop into CTL in vitro. Finally, implanted synthetic microvessels, formed from CRISPR/Cas9-modified EC lacking class II MHC molecules, are significantly protected from CD8+ T cell-mediated destruction in vivo. We conclude that human CD8+ TEM-mediated rejection targeting graft EC class I MHC molecules requires help from CD4+ TEM cells activated by recognition of class II MHC molecules.

Russian traffic sign images dataset

A new public dataset of traffic sign images is presented. The dataset is intended for training and testing the algorithms of traffic sign recognition. We describe the dataset structure and guidelines for working with the dataset, comparing it with the previously published traffic sign datasets. The evaluation of modern detection and classification algorithms conducted using the proposed dataset has shown that existing methods of recognition of a wide class of traffic signs do not achieve the accuracy and completeness required for a number of applications.

Abstract A58: JAK1 deficiency as a novel mechanism of tumor immune escape in uterine cancer

Abstract Recognition of MHC class I antigens on the surface of tumor cells is an essential process in the effector phase of CD8+ cytotoxic T lymphocyte (CTL)-mediated anti-tumor response. Presentation of MHC class I antigens on tumor cells is regulated by the JAK1/JAK2-mediated interferon-γ signaling pathway. We analyzed the targeted exome sequencing data of 3,274 human tumors from 48 different tissues in the Total Cancer Care (TCC) tumor bank and found JAK1 truncating mutations in 36 of 635 gynecologic tumors. The highest JAK1 truncating mutation rate (9.5%) was found in endometrial cancer. These truncating mutations result in the loss of the JAK1 protein tyrosine kinase (PTK) domain that is located in the C-terminal region. JAK1 truncating mutations in cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE) databank also occur most often in endometrial cancer cells. Analysis of mutation sites identified three mutation hot spots. Re-sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed JAK1 mutations and revealed that these JAK1 mutations are somatic. Besides JAK1, recurrent JAK2 loss-of-function (LOF) mutations were also found in TCC tumors but at lower rates. Similar to JAK1, the highest rate of LOF JAK2 mutations was found in endometrial/uterine cancer. No JAK1 or JAK2 truncating mutation was identified in 130 samples from hematological malignancies. Functional assays showed that JAK1 deficient cancer cells were defective in interferon-γ-induced expression of tumor antigen processing machinery proteins LMP2 and TAP1 and cell surface expression of HLA molecules. These data identify recurrent JAK1 deficiency in endometrial cancer that impairs tumor antigen presentation by the MHC class I complex to CTLs. While PTKs have been perceived mostly as oncogenes and PTK inhibitors, including JAK inhibitors, have been developed for cancer therapy, our findings suggest that JAK1 is a novel tumor suppressor and that LOF JAK1 mutations allow tumor immune escape. Our findings also raise caution about the use of JAK inhibitors as therapeutic agents in solid tumors. Citation Format: Yuan Ren, Yonghong Zhang, Richard Z. Liu, David A. Fenstermacher, Kenneth L. Wright, Jamie K. Teer, Jie Wu. JAK1 deficiency as a novel mechanism of tumor immune escape in uterine cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A58.

A bird's eye view of NK cell receptor interactions with their MHC class I ligands.

The surveillance of target cells by natural killer (NK) cells utilizes an ensemble of inhibitory and activating receptors, many of which interact with major histocompatibility complex (MHC) class I molecules. NK cell recognition of MHC class I proteins is important developmentally for the acquisition of full NK cell effector capacity and during target cell recognition, where the engagement of inhibitory receptors and MHC class I molecules attenuates NK cell activation. Human NK cells have evolved two broad strategies for recognition of human leukocyte antigen (HLA) class I molecules: (i) direct recognition of polymorphic classical HLA class I proteins by diverse receptor families such as the killer cell immunoglobulin-like receptors (KIRs), and (ii) indirect recognition of conserved sets of HLA class I-derived peptides displayed on the non-classical HLA-E for recognition by CD94-NKG2 receptors. In this review, we assess the structural basis for the interaction between these NK receptors and their HLA class I ligands and, using the suite of published KIR and CD94-NKG2 ternary complexes, highlight the features that allow NK cells to orchestrate the recognition of a range of different HLA class I proteins.

Addressing imbalanced data with argument based rule learning

In this paper we focus on improving rule based classifiers learned from class imbalanced data by incorporating expert knowledge into the learning process. Applying expert knowledge should overcome limitations of standard methods for imbalanced data when minority classes contain many rare examples and outliers. It should also improve the minority class while maintaining better classification accuracy of the majority classes than the standard methods. Unlike existing proposals for integrating global expert knowledge into rule induction, the class imbalance requires considering local characteristics of class distributions. Therefore, we consider argument based learning, where a domain expert can annotate (explain) some of learning examples to describe reasons for assigning them to specific classes. Using local arguments should improve the interpretability of rules and their consistency with the domain knowledge, and should also result in a better recognition of the minority class. The main aim of our study is to show how argument based learning can be adapted to learn rules from imbalanced data. To achieve it, we introduce a new argument based rule induction algorithm ABMODLEM with a specialized classification strategy for imbalanced classes. Then, we propose new methods for identifying the examples which should be explained by an expert. They exploit the idea of active learning with the query by an ensemble. The proposed approach has been evaluated in an extensive computational experiment. Results show that argument based learning improves the minority class recognition, especially for difficult data distributions with rare examples and outliers. Moreover, ABMODLEM is compared against standard rule classifiers and their extensions with SMOTE preprocessing.

The distal upstream promoter in Ly49 genes, Pro1, is active in mature NK cells and T cells, does not require TATA boxes, and displays enhancer activity.

Missing self recognition of MHC class I molecules is mediated in murine species primarily through the stochastic expression of CD94/NKG2 and Ly49 receptors on NK cells. Previous studies have suggested that the stochastic expression of Ly49 receptors is achieved through the use of an alternate upstream promoter, designated Pro1, that is active only in immature NK cells and operates via the mutually exclusive binding of transcription initiation complexes to closely opposed forward and reverse TATA boxes, with forward transcription being transiently required to activate the downstream promoters, Pro2/Pro3, that are subsequently responsible for transcription in mature NK cells. In this study, we report that Pro1 transcripts are not restricted to immature NK cells but are also found in mature NK cells and T cells, and that Pro1 fragments display strong promoter activity in mature NK cell and T cell lines as well as in immature NK cells. However, the strength of promoter activity in vitro does not correlate well with Ly49 expression in vivo and forward promoter activity is generally weak or undetectable, suggesting that components outside of Pro1 are required for efficient forward transcription. Indeed, conserved sequences immediately upstream and downstream of the core Pro1 region were found to inhibit or enhance promoter activity. Most surprisingly, promoter activity does not require either the forward or reverse TATA boxes, but is instead dependent on residues in the largely invariant central region of Pro1. Importantly, Pro1 displays strong enhancer activity, suggesting that this may be its principal function in vivo.

Litigating Abortion Access Cases in the Post-Windsor World

Exploring how to apply lessons learned from successful challenge to federal Defense of Marriage Act (DOMA), not only to ongoing marriage equality work but also reproductive rights work, is a productive and important endeavor, given similarities between two. An overarching similarity is that two movements are grounded in many of same core values: valuing human dignity, personal decision-making, and fairness. As plurality opinion by Justices O'Connor, Kennedy, and Souter in Planned Parenthood of Southeastern Pennsylvania v. Casey states, Our cases recognize the right of individual, married or single, to be free from unwarranted governmental intrusion into matters so fundamentally affecting a person as decision whether to bear or beget a child. Our precedents respected private realm of family life which state cannot enter. These matters, involving most intimate and personal choices a person may make in a lifetime, choices central to personal dignity and autonomy, are central to liberty protected by Fourteenth Amendment. At heart of liberty is right to define one's own concept of existence, of meaning, of universe, and of mystery of human life. Beliefs about these matters could not define attributes of personhood were they formed under compulsion of State. (1) Concerns about human dignity and respect for personal choices similarly informed Court's majority decision, authored by Justice Kennedy, in United States v. Windsor. The State's power in defining marital relation is of central relevance in this case quite apart from principles of federalism. Here State's decision to give this class of persons right to marry conferred upon them a dignity and status of immense import. When State used its historic and essential authority to define marital relation in this way, its role and its power in making decision enhanced recognition, dignity, and protection of class in their own community.... [DOMA's treatment of state-sanctioned same-sex marriages] places same-sex couples in an unstable position of being in a second-tier marriage. The differentiation demeans couple, whose moral and sexual choices Constitution protects, and whose relationship State has sought to dignify.... The federal statute is invalid, for no legitimate purpose overcomes purpose and effect to disparage and to injure those whom State, by its marriage laws, sought to protect in personhood and dignity. (2) There are other similarities between battles for marriage equality and reproductive rights, and also some very significant differences. My observations focus on reproductive rights litigation--and especially litigation to protect ability of women to continue to access abortion and exercise their reproductive rights in that context. I will highlight some key differences, as well as key similarities, confronted in that litigation as compared to marriage equality litigation. One key difference between two contexts is that in reproductive rights area, we are fighting to preserve existing precedent. In 1973, in Roe v. Wade, U.S. Supreme Court recognized that Federal Constitution, through Due Process Clause, protects a woman's right to determine whether to continue a pregnancy. (3) Since that time, opponents of women's right to reproductive decision-making have engaged in non-stop efforts to eviscerate and eliminate that right, seeking to make exercise of that constitutional right increasingly difficult and seeking reversal of decision in Roe. In contrast, marriage equality litigation is seeking to gain court recognition that Federal Constitution protects right of same-sex couples to marry and to have those marriages treated equally to marriages of opposite-sex couples. …

Evolution and Immunogenetics of Natural Killer Cell Receptors in Health and Disease

Natural killer (NK) cells are phenotypically diverse lymphocytes that contribute to innate immunity, adaptive immunity and placental reproduction. Unlike B and T cells, NK cells do not use rearranging genes to make diverse antigen receptors that are clonally expressed. Instead, NK cells express diverse combinations of a variety of receptors that are encoded by conventional non-rearranging genes. Several of these receptors are specific for conserved and variable determinants of major histocompatibility complex (MHC) class I molecules. In humans, the killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of NK-cell receptors that recognize determinants of human leukocyte antigen (HLA)-A, B and C, the polymorphic human MHC class I molecules. HLA-A, B and C are the most polymorphic of human genes, and they correlate with susceptibility to a wide range of diseases and clinical outcomes, including allogeneic hematopoietic cell transplantation (HCT). During NK-cell development, interactions between epitopes of HLA class I and KIR educate the NK cells to recognize the normal expression of these epitopes on healthy cells, and to respond to unhealthy cells in which that expression is perturbed. In the context of HCT, certain types of HLA class I mismatch enable donor-derived NK cells to make an alloreactive and beneficial graft-versus-leukemia response. Although it is likely that all placental mammals have NK cells, only a small minority of these species has a diverse KIR family like that in humans. These comprise the simian primates: New World monkeys, Old World monkeys and the great apes. Under pressure from diverse and rapidly evolving pathogens, both the MHC class I and KIR gene families have been driven to evolve rapidly. Consequently, much of their character is species-specific. This is especially true for the human KIR gene family, which is qualitatively different from that of our closest relatives, the chimpanzees. Whereas chimpanzee KIR haplotype diversity represents variations on a theme of genes encoding robust MHC class I receptors, humans have an even balance between group A KIR haplotypes encoding robust HLA class I receptors and group B KIR haplotypes encoding receptors that, to varying degree, have been subject to natural selection for reduced functional recognition of HLA class I. A balance of A and B is present in all human populations and thus appears essential for the long-term survival and competitiveness of human communities. Whereas the A KIR haplotypes correlate with successful defense against viral infection, maternal B KIR haplotypes correlate with reproductive success and donor B KIR haplotypes improve the outcome of allogeneic HCT as therapy for acute myeloid leukemia. DisclosuresNo relevant conflicts of interest to declare.