Foxp3+ Regulatory and Conventional CD4+ T Cells Display Similarly High Frequencies of Alloantigen-Reactive Cells

Foxp3+ regulatory T cells (Tregs) play a major role in acquired immune tolerance to allogenic transplants. Their suppressive activity is thought to require T cell receptor (TCR)-driven antigen recognition; little, however, is known about the fraction of Tregs able to recognize alloantigens within this T cell subset primarily educated against self-antigens. Performing transfer experiments of Tregs or conventional T cells (Tconv) into both lymphoreplete and lymphopenic mice, we observed a similarly high proportion of cells signaling through their TCR and proliferating in allogenic hosts. Furthermore, using an in vivo proliferation assay with limited T cell numbers infused into lymphopenic mice, we found that the overall frequency of alloreactive Tregs was similar if not higher to that of alloreactive Tconv. Overall our study highlights a noticeably high level of alloreactive Foxp3+ regulatory T cells accounting for their predominant role in transplantation tolerance

Homéostasie et mécanisme d'action in vivo des lymphocytes T régulateurs CD4+CD25+Foxp3+ chez la souris

Homéostasie et mécanisme d action in vivo des lymphocytes T régulateurs CD4+CD25+Foxp3+ chez la souris Parmi les différentes sous populations de cellules T, les cellules T régulatrices CD4+CD25+ (Tregs), gouvernées par le facteur de transcription Foxp3, représentent un lignage unique de cellules dédiées au maintien de la tolérance immune au soi. Des travaux préalables au sein du laboratoire avaient pu montrer leur potentialité dans le cadre de protocoles d induction de tolérance à long terme en thérapie génique ou cellulaire vis-à-vis d un antigène donné chez la souris. Les travaux présentés ici ont porté sur divers aspects fondamentaux du mécanisme d action et de l homéostasie de ces cellules in vivo dans ces modèles murins non lymphopéniques. Dans un premier temps, nous avons pu montrer que l action de Tregs spécifiques de l antigène de rejet, dans les deux modèles étudiés, passait par une altération profonde de l activation de la réponse T CD8+, conduisant à une inhibition presque totale de la prolifération et de la différentiation de ces cellules in vivo. Nous avons ensuite étudié les modes de recrutement possible in vivo de Tregs spécifiques d un antigène et nous avons pu montrer que la simple injection par voie intraveineuse d un peptide restreint aux molécules du CMH de classe II suffisait à induire l activation et l accumulation sélective de T CD4+ CD25+ spécifiques de cet antigène en périphérie. Enfin, nous avons tiré profit d un modèle murin de souris Foxp3eGFP, développé en collaboration avec le laboratoire du Dr Bernard MALISSEN (CIML Marseille) et dans lequel la protéine GFP a été insérée en aval du locus foxp3 endogène, pour mettre en évidence pour la première fois un phénomène de conversion périphérique de T naïf en Treg dans un répertoire polyclonal.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Mémoire immunitaire contre le SARS-CoV-2: Des anticorps contre l’infection initiale et des lymphocytes B à mémoire contre les infections futures

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Correction: Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells.

[This corrects the article DOI: 10.1371/journal.pone.0157822.]

Foxp3+ regulatory T cells (Tregs) play a major role in acquired immune tolerance to allogenic transplants. Their suppressive activity is thought to require T cell receptor (TCR)-driven antigen recognition; little, however, is known about the fraction of Tregs able to recognize alloantigens within this T cell subset primarily educated against self-antigens. Performing transfer experiments of Tregs or conventional T cells (Tconv) into both lymphoreplete and lymphopenic mice, we observed a similarly high proportion of cells signaling through their TCR and proliferating in allogenic hosts. Furthermore, using an in vivo proliferation assay with limited T cell numbers infused into lymphopenic mice, we found that the overall frequency of alloreactive Tregs was similar if not higher to that of alloreactive Tconv. Overall our study highlights a noticeably high level of alloreactive Foxp3+ regulatory T cells accounting for their predominant role in transplantation tolerance.

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BALANCING THE STATIONS OF A SELF SERVICE “BIKE HIRE” SYSTEM

This paper is motivated by operating self service transport systems that flourish nowadays. In cities where such systems have been set up with bikes, trucks travel to maintain a suitable number of bikes per station. It is natural to study a version of the C-delivery TSP defined by Chalasani and Motwani in which, unlike their definition, C is part of the input: each vertex v of a graph G = (V, E) has a certain amount xv of a commodity and wishes to have an amount equal to yv (we assume that v∈V xv = v∈V yv and all quantities are assumed to be integers); given a vehicle of capacity C, find a minimal route that balances all vertices, that is, that allows to have an amount yv of the commodity on each vertex v. This paper presents among other things complexity results, lower bounds, approximation algorithms, and a polynomial algorithm when G is a tree

A key aspect to consider for vaccinal protection is the induction of a local line of defense consisting of nonrecirculating tissue-resident memory T cells (TRM), in parallel to the generation of systemic memory CD8+ T cell responses. The potential to induce TRM has now been demonstrated for a number of pathogens and viral vectors. This potential, however, has never been tested for recombinant adeno-associated virus (rAAV) vectors, which are weakly inflammatory and poor transducer of dendritic cells. Using a model rAAV2/1-based vaccine, we determined that a single intradermal immunization with rAAV2/1 vectors in mice induces fully functional TRM at the local site of immunization. The optimal differentiation of rAAV-induced transgene-specific skin TRM was dependent on local transgene expression and additional CD4+ T cell help. Transgene expression in dendritic cells, however, appeared to be dispensable for the priming of transgene-specific skin TRM, suggesting that this process solely depends on the cross-presentation of transgene products. Overall, this study provides needed information to properly assess rAAV vectors as T cell-inducing vaccine carriers.IMPORTANCE rAAVs display numerous characteristics that could make them extremely attractive as vaccine carriers, including an excellent safety profile in humans and great flexibility regarding serotypes and choice of target tissue. Studies addressing the ability of rAAV to induce protective T cell responses, however, are scarce. Notably, the potential to induce a tissue-resident memory T cell response has never been described for rAAV vectors, strongly limiting further interest for their use as vaccine carriers. Using a model rAAV2/1 vaccine delivered to the skin, our study demonstrated that rAAV vectors can induce bona fide skin resident TRM and provides additional clues regarding the cellular mechanisms underlying this process. These results will help widen the field of rAAV applications.

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Intradermal Immunization with rAAV1 Vector Induces Robust Memory CD8+ T Cell Responses Independently of Transgene Expression in DCs

International audienceRecombinant adeno-associated viral (rAAV) vectors exhibit interesting properties as vaccine carriers for their ability to induce long-lasting antibody responses. However, rAAV-based vaccines have been suggested to trigger functionally impaired long-term memory CD8+ T cell responses, in part due to poor dendritic cell (DC) transduction. Such results, albeit limited to intramuscular immunization, undermined the use of rAAV as vaccine vehicles against intracellular pathogens. We report here that intradermal immunization with a model rAAV2/1-based vaccine drives the development of bona fide long-term memory CD8+ T cell responses. The intradermal route of immunization and the presence of potent major histocompatibility complex (MHC) class II responses showed synergistic effects on the overall quantity and quality of systemic long-term effector memory transgene-specific CD8+ T cells being generated against the transgene. Of key interest, we found that the induction of memory cytotoxic T lymphocytes (CTLs) following intradermal immunization was solely dependent on the cross-presentation of skin-expressed transgene products, which appeared highly enhanced as compared to muscle-expressed transgene products. Overall our results highlight key tissue-specific differences in transgene presentation pathway requirements of importance for the design of rAAV-based T cell-inducing vaccines