Valentin Quiniou

Women represent about 80% of patients with autoimmune diseases. This may partly result from sex-based differences in T cell receptor (TCR) selection during thymocyte development, potentially influenced by hormones and the lower expression of the Autoimmune Regulator (AIRE) transcription factor in females. To investigate this, we analyzed sex-specific differences in TCR generation and selection. We examined TCR repertoires in double-positive thymocytes and single-positive thymic cells, including CD8 ⁺ and CD4 ⁺ effector T cells and regulatory T cells (Tregs), derived from male and female organ donors. Minimal sex-based differences were observed in V and J gene usage, and there were no notable differences in TCR repertoire diversity, complementarity-determining region 3 (CDR3) length, amino acid composition, or network structure. No TCR sequences were exclusive to either sex. However, female effector T cells exhibited a significantly higher prevalence of TCRs specific to self-antigens implicated in autoimmunity compared to males, while female Tregs showed a reduced frequency of such TCRs. These differences were not observed for TCRs targeting self-antigens unrelated to autoimmunity or antigens associated with cancer or viruses. Our findings identify a sex-specific imbalance in thymic selection of TCRs with autoimmunity-associated specificities, providing mechanistic insight into the increased susceptibility of women to autoimmune diseases.

Séléction de CD8 non conventionnel au cours de la thymopoïèse humaine: La spécificité est la caractéristique de la réponse immunitaire adaptative. Pour les cellules T, la spécificité est médiée par les récepteurs des cellules T (TCR), qui interagissent avec les peptides présentés par les molécules du complexe majeur d'histocompatibilité via leur domaine hypervariable 3 (CDR3). Les TCR sont formés par des réarrangements entre des centaines de gènes alpha et bêta, générant théoriquement plus de 1019 séquences différentes. La sélection de TCR pendant la thymopoïèse génère pour chaque individu un répertoire d'environ 107 à 108 TCR uniques. La façon dont l'évolution a façonné un processus qui sélectionne les TCR qui répondraient efficacement aux antigènes qui ne sont pas encore présents est une question centrale de l'immunologie. Le paradigme est que la sélection d'un répertoire composé de TCR suffisamment divers devrait toujours fournir une spécificité appropriée pour une réponse immunitaire efficace et pour la mémoire immunitaire. Cependant, cette spécificité est remise en question par des données négligées. En effet, des données expérimentales et épidémiologiques mettent en évidence une immunité hétérologue, c'est-à-dire que l'exposition à un agent permet une protection efficace contre l'infection par un autre agent. Nous montrons ici que, lors de la thymopoïèse humaine, il existe un enrichissement marqué en CDR3 avec des probabilités de génération élevées, partagées entre les individus et spécifiques des peptides viraux. Nos résultats soutiennent une sélection évolutive qui favorise les TCR polyspécifiques pour les réponses antivirales et l'immunité hétérologue.

The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T-cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T-cell maturation in the thymus. Characterizing TCR repertoires across individuals and T-cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T-cell maturation and differentiation. The interindividual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T-cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types. Published by the American Physical Society 2024

Supplementary Figure from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Supplementary Figure from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.Significance:Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy.This article is highlighted in the In This Issue feature, p. 873

Supplementary Figure from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Supplementary Figure from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.Significance:Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy.This article is highlighted in the In This Issue feature, p. 873

Supplementary Table from Plasma CD27, a Surrogate of the Intratumoral CD27–CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma