« Un géant sans bras ni jambes » : Une critique sur la Cour Pénale Internationale

Résumé :Cet essai critique la Cour Pénale Internationale (CPI). Certes, elle a mis à fin l’impunité des crimes internationaux, néanmoins elle reste rongée par la lenteur et l’inefficacité. L’essai identifie les problèmes de la CPI et met leur origine en évidence. En étudiant les racines de la CPI, sa création ainsi que les enjeux de droit international et de politique internationale, on peut identifier les lacunes qu’il convient de combler. J’ai étudié quelques procès du Tribunal Pénal de l’ex-Yougoslavie et de la CPI ainsi que des livres et de nombreux articles sur le droit pénal international et l’histoire de la CPI. Le but de cet essai n’est pas de contester la CPI, son but est de mettre en évidence quelques problèmes, réparables pour certains d’entre eux. On conclut qu’il faut faire beaucoup plus d’études en droit comparatif international et qu’il faut mettre en évidence les enjeux politiques qui entourent la CPI.Abstract:This essay critiques the International Criminal Court (ICC). Although it has brought the impunity of international crimes to an end, the court is wracked with slowness and inefficiency. This essay identifies the ICC’s problems and brings their origins to light. By studying the roots of the ICC, its creation along with the issues of international law and politics, one can identify the gaps that should be filled. I studied several trials of the International Criminal Tribunal of the former Yugoslavia and of the ICC, as well as books and numerous articles about international criminal law and the history of the ICC. The goal of this essay is not to challenge the ICC; the goal is to bring certain problems, some of them reparable, to light. It is concluded that many more international comparative law studies need to be undertaken, and that the political issues that surround the ICC need to be brought to light

Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1

Killer cell immunoglobulin-like receptors (KIRs) play an important role in the activation of natural killer (NK) cells, which in turn contribute to the effective immune control of many viral infections. In the context of HIV infection, the closely related KIR3DL1 and KIR3DS1 molecules, in particular, have been associated with disease outcome. Inhibitory signals via KIR3DL1 are disrupted by downregulation of HLA class I ligands on the infected cell surface and can also be impacted by changes in the presented peptide repertoire. In contrast, the activatory ligands for KIR3DS1 remain obscure. We used a structure-driven approach to define the characteristics of HLA class I-restricted peptides that interact with KIR3DL1 and KIR3DS1. In the case of HLA-B*57:01, we used this knowledge to identify bona fide HIV-derived peptide epitopes with similar properties. Two such peptides facilitated productive interactions between HLA-B*57:01 and KIR3DS1. These data reveal the presence of KIR3DS1 ligands within the HIV-specific peptide repertoire presented by a protective HLA class I allotype, thereby enhancing our mechanistic understanding of the processes that enable NK cells to impact disease outcome. IMPORTANCE Natural killer (NK) cells are implicated as determinants of immune control in many viral infections, but the precise molecular mechanisms that initiate and control these responses are unclear. The activating receptor KIR3DS1 in combination with HLA-Bw4 has been associated with better outcomes in HIV infection. However, evidence of a direct interaction between these molecules is lacking. In this study, we demonstrate that KIR3DS1 recognition of HLA-Bw4 is peptide dependent. We also identify HIV-derived peptide epitopes presented by the protective HLA-B*57:01 allotype that facilitate productive interactions with KIR3DS1. Collectively, these findings suggest a mechanism whereby changes in the peptide repertoire associated with viral infection provide a trigger for KIR3DS1 engagement and NK cell activation

Epitope length variants balance protective immune responses and viral escape in HIV-1 infection

Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B∗27:05. We find that proteasomal activity generates multiple length variants of KK10 (4–14 amino acids), which bind TAP and HLA-B∗27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses. Structural analyses reveal that all epitope forms bind HLA-B∗27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B∗27:05. Common viral escape mutations abolish (L136M) or impair (R132K) production of KK10 and longer epitope forms. Peptide length influences how well the inhibitory NK cell receptor KIR3DL1 binds HLA-B∗27:05 peptide complexes and how intraepitope mutations affect this interaction. These results identify a viral escape mechanism from CTL and NK responses based on differential antigen processing and peptide competition

T-cell Receptor (TCR)-Peptide Specificity Overrides Affinity-enhancing TCR-Major Histocompatibility Complex Interactions

αβ T-cell receptors (TCRs) engage antigens using complementarity-determining region (CDR) loops that are either germ line-encoded (CDR1 and CDR2) or somatically rearranged (CDR3). TCR ligands compose a presentation platform (major histocompatibility complex (MHC)) and a variable antigenic component consisting of a short “foreign” peptide. The sequence of events when the TCR engages its peptide-MHC (pMHC) ligand remains unclear. Some studies suggest that the germ line elements of the TCR engage the MHC prior to peptide scanning, but this order of binding is difficult to reconcile with some TCR-pMHC structures. Here, we used TCRs that exhibited enhanced pMHC binding as a result of mutations in either CDR2 and/or CDR3 loops, that bound to the MHC or peptide, respectively, to dissect the roles of these loops in stabilizing TCR-pMHC interactions. Our data show that TCR-peptide interactions play a strongly dominant energetic role providing a binding mode that is both temporally and energetically complementary with a system requiring positive selection by self-pMHC in the thymus and rapid recognition of non-self-pMHC in the periphery

Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2

Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens

Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition

Natural killer (NK) cells play a key role in immunity, but how HLA class I (HLA-I) and killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/*005/*015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1*005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1*001, *005, and *015 polymorphisms are remote from the KIR3DL1-HLA-I interface, the structures of these three KIR3DL1-HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1*005 correlated with an altered KIR3DL1*005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems

A functional and structural study of HLA-­B*2705 restricted CTL responses associated with delayed HIV-­1 disease progression

The HIV-1 Gag p24 protein contains the HLA class-1 B*2705 restricted epitope KK10, responses to which are associated with delayed progression. Data from in vitro proteasomal digestion studies from our group has shown the production of a number of C-terminally extended and truncated epitopes containing KK10, produced in far higher quantities during proteasomal digestion than this “optimal epitope” and that the amount of antigen made in proteasomal digestion is instrumental in determining the development of immunodominance. This work aims to characterise the contribution of these naturally processed epitope forms to the cellular immune response to this region.Further proteasomal digestion studies have shown that the common KK10 intra-epitope escape mutant sequences R132K and L136M have major effects on epitope production by the proteasome and that a range of short peptides containing the N-terminal of the KK10 sequence are produced in large quantities by the proteasome. Recognition of the KK10 epitope forms by HLA B*2705 HIV-1 patients were characterised ex vivo and show recognition of KK10 epitope forms somewhat independent of the presence of KK10 recognition, we also show cross-recognition between KK10 epitope forms by CD8+ T cells, as well as recognition by CD4+ T-cells. TCR from CD8+ T-cells specific for KK10 epitope forms were found to share common features in the HLA binding CDR hyper-variable loops.Structural studies of the HLA B*2705 molecules in complex with the KK10 epitope forms show a shared binding motif at the N-terminus, and to a lesser extent, the C-terminus of the binding groove which may facilitate cross-recognition of complexes. In addition these studies show a potentially novel binding mode for a 14mer peptide, and refolding of truncated KK10 peptides as short as a 4mer with the HLA B*2705 molecule (crystallisation with a 6mer peptide shown). This demonstrates previously unrecognised flexibility of the HLA class-1 to bind and present peptides of different lengths to T-cells.We show that these HLA B*2705 binding-capable truncated peptides do not induce a CD8+ T-cell response in HLA B*2705 HIV-1 patients and may be able to block CD8+ T-cell responses to the KK10 epitope. This might represent a novel form of viral CTL escape. In addition we observe the presence of KK10 flanking mutations in patient sequences and significant associations between the presence of intra-epitope escape mutations, KK10 recognition and patterns of escape in flanking sequences.Finally we note the reduction in binding of KIR3DL1 to KK10 epitope forms relative to the KK10 epitope-HLA B*2705 complex. The presence of HLA B*2705 and KIR3DL1 associate with improved disease course in HIV-1 though the mechanism through which this occurs has yet to be defined.This thesis is not currently available via ORA

The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations