Natural killer T cell recognition of lipid antigens

Natural killer T cells recognize lipid antigens in the context of CD1 molecules. Recent publications show that this mode of recognition differs substantially from that of classic T-cell receptor peptide-major histocompatibility complex interaction

Gestion des bibliothèques tierces dans un contexte de maintenance logicielle

Software depend on third-party libraries to reduce development and maintenance costs. Developers have access to robust functionalities through an application programming interface designed by these libraries. However, due to the strong relationship with these libraries, developers have to reconsider their position when the software evolves. In this thesis, we identify several re-search problems involving these third-party libraries in a context of software maintenance. More specifically, a library may not satisfy the software new requirements and has to be replaced by anew one. We call this operation a library migration.We leverage three points that characterize the impediments met by developers in this situation.To which library should they migrate ? How to migrate their software ? Who can help them in this case ? This thesis suggests answers and exposes several contributions to these problems. We define three approaches that are evaluated through several case studies. To achieve this work, weuse a methodology based on software evolution analysis to observe and understand how software change. We describe numerous perspectives to overcome the current limitations of our solutions.Les logiciels dépendent de bibliothèques tierces pour réduire les coûts liés à leur développement et à leur maintenance. Elles proposent un ensemble de fonctionnalités robustes dont les développeurs peuvent tirer parti depuis une interface de programmation. Cependant, cette forte dépendance entre un logiciel et ses bibliothèques oblige les développeurs à reconsidérer leur rôle lorsque le logiciel évolue. Dans cette thèse, nous identifions plusieurs problématiques impliquant les bibliothèques tierces dans un contexte de maintenance logicielle. Plus particulièrement, une bibliothèque peut ne plus répondre aux besoins d’un logiciel et doit être remplacée par une nouvelle.Nous nommons cette opération une migration de bibliothèque.Nous soulevons dans ce contexte trois points qui caractérisent les difficultés rencontrées par les développeurs. Vers quelle bibliothèque migrer ? Comment appliquer la migration ? Avec l’aide de quels développeurs ? Cette thèse discute de solutions et apporte des contributions autour de ces problèmes. Nous présentons plusieurs approches et les évaluons lors de différents cas d’étude. L’analyse de l’évolution logicielle sera notre support de travail, dont la méthodologie est basée sur l’observation des changements de logiciels. Nous décrivons les limites actuelles de nos contribu-tions et ouvrons des perspectives futures pour enrichir l’état de l’art dans ce domain

Distinct Functional Lineages of Human Vα24 Natural Killer T Cells

CD1d-restricted autoreactive natural killer (NK)T cells have been reported to regulate a range of disease conditions, including type I diabetes and immune rejection of cancer, through the secretion of either T helper (Th)2 or Th1 cytokines. However, mechanisms underlying Th2 versus Th1 cytokine secretion by these cells are not well understood. Since most healthy subjects express <1 NKT cell per 1,000 peripheral blood lymphocytes (PBLs), we devised a new method based on the combined used of T cell receptor (TCR)-specific reagents α-galactosylceramide (αGalCer) loaded CD1d-tetramers and anti-Vα24 monoclonal antibody, to specifically identify and characterize these rare cells in fresh PBLs. We report here that CD4+ and CD4−CD8− (double negative [DN]) NKT cell subsets represent functionally distinct lineages with marked differences in their profile of cytokine secretion and pattern of expression of chemokine receptors, integrins, and NK receptors. CD4+ NKT cells were the exclusive producers of interleukin (IL)-4 and IL-13 upon primary stimulation, whereas DN NKT cells had a strict Th1 profile and prominently expressed several NK lineage receptors. These findings may explain how NKT cells could promote Th2 responses in some conditions and Th1 in others, and should be taken into consideration for intervention in relevant diseases

Characterization of the early stages of thymic NKT cell development

Upon reaching the mature heat stable antigen (HSA)low thymic developmental stage, CD1d-restricted Vα14-Jα18 thymocytes undergo a well-characterized sequence of expansion and differentiation steps that lead to the peripheral interleukin-4/interferon-γ–producing NKT phenotype. However, their more immature HSAhigh precursors have remained elusive, and it has been difficult to determine unambiguously whether NKT cells originate from a CD4+CD8+ double-positive (DP) stage, and when the CD4+ and CD4−CD8− double-negative (DN) NKT subsets are formed. Here, we have used a CD1d tetramer-based enrichment strategy to physically identify HSAhigh precursors in thymuses of newborn mice, including an elusive DPlow stage and a CD4+ stage, which were present at a frequency of ∼10−6. These HSAhigh DP and CD4+ stages appeared to be nondividing, and already exhibited the same Vβ8 bias that characterizes mature NKT cells. This implied that the massive expansion of NKT cells is separated temporally from positive selection, but faithfully amplifies the selected TCR repertoire. Furthermore, we found that, unlike the DN γδ T cells, the DN NKT cells did not originate from a pTα-independent pathway bypassing the DP stage, but instead were produced during a short window of time from the conversion of a fraction of HSAlow NK1.1neg CD4 cells. These findings identify the HSAhigh CD4+ stage as a potential branchpoint between NKT and conventional T lineages and between the CD4 and DN NKT sublineages