CD4+ T Cell Help Is Mandatory for Naive and Memory Donor-Specific Antibody Responses: Impact of Therapeutic Immunosuppression

Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients’ spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal

Evaluation economique de la fracture dyaphysaire du femur de l'enfant d'age scolaire traitee orthopediquement

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : DO 4670 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Maize<i>(Zea mays</i>L.) interaction with the arbuscular mycorrhizal fungus<i>Rhizophagus irregularis</i>allows mitigation of nitrogen deficiency stress: physiological and molecular characterization

International audienceMaize is currently the most productive cereal crop in the world (www.faostat.org). Maize can form a symbiotic relationship with the Arbuscular Mycorrhizal Fungus MF, Rhizophagus irregularis. In this relationship, the fungus provides the plant with additional water and mineral nutrients, while the plant supplies carbon compounds to the fungus. Two maize lines were studied, and they exhibited contrasting responses to AMF inoculation based on their physiological and molecular characteristics. Interestingly, the beneficial effects of the AMF were observed mainly under conditions of limited N fertilization. Under such conditions, the AMF helped maintain plant biomass production even when there was a significant reduction in N supply. The availability of nitrogen was found to be a crucial factor influencing all the traits studied. This suggests that the level of N supply plays a pivotal role in determining how the maize plants interact with the AMF. Despite the two maize lines showing different transcriptomic and metabolomic responses to R. irregularis, their agro-physiological traits remained similar. This indicates that while there may be genetic differences in how the plants respond at the molecular level, the overall growth and productivity outcomes are comparable. Both the plant and fungal transcriptomes were more significantly influenced by the level of N nutrition rather than the specific maize genotype. This suggests that N availability has a more profound impact on gene expression in both organisms than the genetic makeup of the maize plant. To understand the metabolic implications of this symbiotic relationship, we integrated transcriptomic data into a multi-organ Genome-scale metabolic model (GSM) called iZMA6517 based on a stoichiometric approach. This modelling approach highlighted nucleotide and ureides metabolism as previously unrecognized factors contributing to the symbiotic N nutrition facilitated by R. irregularis, thereby enhancing maize growth

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<p>Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients’ spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal.</p