ABSTRACT
T cells form immunological synapses with professional antigen-presenting cells (APCs) resulting in T cell activation and the acquisition of peptide antigen-MHC (pMHC) complexes from the plasma membrane of the APC. They thus become APCs themselves. We investigate the functional outcome of T-T cell antigen presentation by CD4 T cells and find that the antigen-presenting T cells (Tpres) predominantly differentiate into regulatory T cells (Treg), whereas T cells that have been stimulated by Tpres cells predominantly differentiate into Th17 pro-inflammatory cells. Using mice deficient in pMHC uptake by T cells, we show that T-T antigen presentation is important for the development of experimental autoimmune encephalitis and Th17 cell differentiation in vivo. By varying the professional APC:T cell ratio, we can modulate Treg versus Th17 differentiation in vitro and in vivo, suggesting that T-T antigen presentation underlies proinflammatory responses in conditions of antigen scarcity.
Subject(s)
Antigen Presentation/immunology , Antigens/metabolism , Cell Polarity/immunology , Th17 Cells/immunology , Animals , CD28 Antigens/metabolism , Cell Differentiation/immunology , Cell Membrane/metabolism , Dendritic Cells/immunology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Gene Expression Regulation , Genome , Histocompatibility Antigens Class II/immunology , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/immunology , Transcription, Genetic , Trogocytosis , rho GTP-Binding Proteins/deficiency , rho GTP-Binding Proteins/metabolismABSTRACT
Signal strength controls the outcome of αß T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2-/- mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We show that MOG-specific T cells in Rras2-/- mice have reduced affinity for MOG/I-Ab tetramers, suggesting that enhanced negative selection leads to selection of TCRs with lower affinity for the self-MOG peptide. An analysis of the TCR repertoire shows alterations that mostly affect the TCRα variable (TRAV) locus with specific VJ combinations and CDR3α sequences that are absent in Rras2-/- mice, suggesting their involvement in autoimmunity.
Subject(s)
Clonal Selection, Antigen-Mediated , Encephalomyelitis, Autoimmune, Experimental/immunology , Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor/immunology , Membrane Proteins/immunology , Monomeric GTP-Binding Proteins/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Animals , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/pathology , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor/immunology , Membrane Proteins/genetics , Mice , Mice, Knockout , Monomeric GTP-Binding Proteins/genetics , Myelin-Oligodendrocyte Glycoprotein/adverse effects , Myelin-Oligodendrocyte Glycoprotein/pharmacologyABSTRACT
The original version of this Article contained an error in the spelling of the author José María González-Granado, which was incorrectly given as José María Gozález-Granado. This has now been corrected in both the PDF and HTML versions of the Article.
ABSTRACT
Bacterial phagocytosis and antigen cross-presentation to activate CD8+ T cells are principal functions of professional antigen presenting cells. However, conventional CD4+ T cells also capture and kill bacteria from infected dendritic cells in a process termed transphagocytosis (also known as transinfection). Here, we show that transphagocytic T cells present bacterial antigens to naive CD8+ T cells, which proliferate and become cytotoxic in response. CD4+ T-cell-mediated antigen presentation also occurs in vivo in the course of infection, and induces the generation of central memory CD8+ T cells with low PD-1 expression. Moreover, transphagocytic CD4+ T cells induce protective anti-tumour immune responses by priming CD8+ T cells, highlighting the potential of CD4+ T cells as a tool for cancer immunotherapy.
Subject(s)
Antigen Presentation/immunology , Antigens, Bacterial/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Animals , Cells, Cultured , Cross-Priming/immunology , Cytotoxicity, Immunologic/immunology , Immunologic Memory/immunology , Immunological Synapses/immunology , Mice, Inbred C57BL , Mice, Transgenic , Phagocytosis/immunology , Programmed Cell Death 1 Receptor/immunologyABSTRACT
Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities.
