Immune recognition and immune tolerance - Timothy Tree.pdf

Immune tolerance and immune recognition Learning objectives: i. Understand the importance of self/non-self recognition ii. Outline the processes involved in establishing immune tolerance iii. Describe the process of immune recognition and the evolution of the adaptive immune response to fore...

Immune tolerance and immune recognition Learning objectives: i. Understand the importance of self/non-self recognition ii. Outline the processes involved in establishing immune tolerance iii. Describe the process of immune recognition and the evolution of the adaptive immune response to foreign pathogens Immune tolerance and immune recognition Dr TimTree Department of Immunobiology Faculty of Life Sciences & Medicine Topics The importance of self/non-self recognition The processes involved in establishing immune tolerance The process of immune recognition and the evolution of the adaptive immune response to foreign pathogens The importance of self/non-self recognition Main cellular players in the immune response adaptive B cell CD4 CD8 T cell T cell Provide help Kill infected cells Make antibody Antigen presenting cells innate Neutrophil Mac DC Antigen presentation Killing pathogens Killing pathogens Antigen presentation Reminder: TCR diversity is huge and generated by random events The TCR is generated by gene rearrangement Random joining x combination of hetrodimers x other mechanisms = 4.5x109 Recognition of unseen pathogens Random TCR diversity makes self-reactivity possible CD8+ CD8+ T cell T cell Killing Killing Virus infected cell Endocrine cell The processes involved in establishing immune tolerance  Immune tolerance prevents autoreactivity but permits appropriate anti-pathogen responses Immunodeficiency Autoimmunity T cells develop in the thymus Cortex Medulla Seeded by bone marrow derived precursors Multi-lobular containing organized zones Contains several specialized cell types Thymic education: T cells acquire ‘tools of the trade’ CD4 TCR Thymocyte CD8 TCR Receptor: Expression of a functional TCR Accessory molecules: Expression of either CD4 or CD8 -ability to use them safely & within the laws of MHC restriction Expression of a functional TCR TCR genes rearranged Cells with non-functional TCR die Thymocyte CD4 CD8 a b TCR Positive selection for self MHC Affinity for MHCII No affinity for MHCI&II Affinity for MHCI Thymocyte Thymocyte Thymocyte CD4 CD8 CD4 CD8 CD4 CD8 MHCII MHCI Thymic Cortex CD4 CD8 Apoptosis Positive selection for self MHC ✔ ✔ ✖ Negative selection to eliminate high affinity self-reactive T cells Low/moderate affinity CD4 CD4 High affinity Thymic medullary epithelial cells (TMECs) Activation CD4 induced death TMECs express a variety of tissue restricted antigens TMECs possess transcription factors that allow them to express TRAs Examples of peripheral proteins Peripheral tissue expressed by TMECs represented Serum amyloid P Liver Trypsin Pancreas Insulin Islets of Langerhans Crystallin Eye Thyroglobulin Thyroid Failure of TMECs express tissue restricted antigens leads to autoimmune diseases e.g. APS type 1 Thymic education Functional TCR? No Yes TCR able to interact with self MHC? No Yes TCR has high affinity for self antigen? Yes No peripheral circulation (