Tolerance induction in memory CD4 T cells is partial and reversible
| Autor: | Megan K. L. MacLeod, Jennifer L. Matsuda, Shaima Al Khabouri, Laurent Gapin, F. Morton, Paul Garside, John W. Kappler, Phillipa Marrack, Eric T. Clambey, Joshua I. Gray, Thomas D. Otto |
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| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine DNA Repair Transcription Genetic Cell division DNA repair proliferation T cell medicine.medical_treatment Immunology Autoimmunity Biology Lymphocyte Activation medicine.disease_cause Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Antigen Immune Tolerance medicine Gene silencing Animals Immunology and Allergy Antigens mitotic catastrophe Cell Proliferation Inflammation tolerance Cell Cycle Original Articles Cell biology Mice Inbred C57BL memory CD4 T cells Tolerance induction 030104 developmental biology medicine.anatomical_structure Cytokines Original Article Female Immunologic Memory Adjuvant 030215 immunology |
| Zdroj: | Immunology |
| ISSN: | 1365-2567 0019-2805 |
| Popis: | We have examined the response of memory CD4 T cells to tolerogenic signals. Although memory CD4 T cells could respond to antigen delivered without adjuvant, they undergo cell death upon further restimulation. Our data suggest that the Tcells die as a consequence of mitotic catastrophe that occurs when cells are unable to complete cell division. Summary Memory T cells respond rapidly in part because they are less reliant on a heightened levels of costimulatory molecules. This enables rapid control of secondary infecting pathogens but presents challenges to efforts to control or silence memory CD4 T cells, for example in antigen‐specific tolerance strategies for autoimmunity. We have examined the transcriptional and functional consequences of reactivating memory CD4 T cells in the absence of an adjuvant. We find that memory CD4 T cells generated by infection or immunisation survive secondary activation with antigen delivered without adjuvant, regardless of their location in secondary lymphoid organs or peripheral tissues. These cells were, however, functionally altered following a tertiary immunisation with antigen and adjuvant, proliferating poorly but maintaining their ability to produce inflammatory cytokines. Transcriptional and cell cycle analysis of these memory CD4 T cells suggests they are unable to commit fully to cell division potentially because of low expression of DNA repair enzymes. In contrast, these memory CD4 T cells could proliferate following tertiary reactivation by viral re‐infection. These data indicate that antigen‐specific tolerogenic strategies must examine multiple parameters of Tcell function, and provide insight into the molecular mechanisms that may lead to deletional tolerance of memory CD4 T cells. |
| Databáze: | OpenAIRE |
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