Th1 and Th2 immune responses Part 1

Learning outcomes By the end of this session students should be able to Describe the difference between CD8 cytotoxic T cells and CD4 T helper cells Explain how cytotoxic T cells are activated Define the different T helper subtypes Explain the importance of the Th1/Th2 balance

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T cell maturation T cell goes through different stages of development DP express both CD4 and CD8 TCR Each cell has a unique TCR TCR has two binding sites One for MHC One for antigen Reactivity with MHC on stromal cells checked T cells need to bind to be able to bind to MHC Those that cannot bind are negatively selected and die CD4 or CD8 TCR are chosen depending on binding to MHC TCR exposed to self antigens Negative selection of any T cells that bind too strongly to self antigens CD8+ cytotoxic T cells CD4+ T helper cells Naive until activated by APC (usually dendritic cells)

Intracellular pathogens can infect cells and start to replicate Fc Receptor Phagocyte Pathogen Intracellular pathogens can infect cells and start to replicate Infected cell Pathogen Pathogen Phagocytosis Opsinisation

CD8 - Cytotoxic T cells Naïve CD8 T cells recognise cells which are infected with intracellular pathogens especially viruses The viral peptides are presented on the MHC I complex CD8 cell becomes activated and differentiate into a cytotoxic T cell Cytotoxic T cell will kill the target cell (by inducing apoptosis) However, this process is very tightly regulated

Activation of cytotoxic T cells APC (usually dendritic cells) need to become licensed By CD4+ cells Activation of Toll like receptors Activation of CD8+ cell to become a cytotoxic T cell requires CD8+ cell must bind via MHCI/antigen recognition on licensed APC A co-stimulatory signal by the CD28 CD80/86 interaction IL2 binding to CD8 cell CD4+ cell help enhances these signals

Licensing of APC and differentiation to CTL Th1 or Th17 TCR CD40L CD8+ TCR CD28 IL2 MHC II MHC I CD40 ++ CD80/86 TLR Sequential Simultaneous TLR Antigen Presenting Cell

CD4 - T helper cell activation CD 4 T cells can differentiate in to a variety of subsets Th1 - control bacteria that infect macrophages and reside in vesicles Th2 - control parasitic infections such as helminths rather than intracellular infections Th17- stimulate neutrophil responses to eliminate bacteria and fungi Regulatory T cells - supress T cell responses T follicular helper - provide help to B cells Which type of T cell a naïve cell will differentiate to will depend on cytokine signals Subsets defined by the combination of cytokines that they secrete Effector T helper cells work outside the lymphoid tissues at sites of infection

Activation of CD4 cells

Th1 and Th2 activation IL4 Mast cell Dendritic cell IL12 CD4+ Th0 NK cell IL4 IFN Pathogen IL2 IFN LTA IL4 IL5 IL10 IL13 Th1 Th2 Macrophage

Th1 and Th2 cytokines

Th1 and macrophage activation Th1 differentiation is polarised by IL12, IL18 and IFN IL12 produced by APC after TLR activation by pathogen IFN produced by activated T cells enhances APC IL12 production APC produces TNF which binds to TNF receptor which sensitisers the macrophage to IFN 

Licensing of APC and differentiation to CTL IL2 ++ CD4+ TCR CD40L MHC II TNFR IFN CD40 TNF TLR TLR Antigen Presenting Cell

Th1 and macrophage activation Th1 differentiation is polarised by IL12, IL18 and IFN IL12 produced by APC after TLR activation by pathogen IFN produced by activated T cells enhances APC IL12 production APC produces TNF which binds to TNF receptor which sensitisers the macrophage to IFN  IFN activates macrophages to:Increase microbicidal activity Upregulate the level of MHCII Increases secretion of IL12 Induces antibody class switching in B cells Promotes differentiation of CTL Contribute to delayed type hypersensitivity Macrophage activation is inhibited by Th2 cytokines

Problems in the T cell- macrophage response Mice with destroyed IFN or CD40 susceptible to sublethal doses of Mycobacteria and Leishmania Mice lacking TNF receptors susceptible to vaccinia virus Chronically infected macrophages may lose ability to become activated Depletion of T cells lead to an increase in pathogens that infect macrophages

Example of the wrong Th response Th1 responses lead to cell mediated immunity Th2 responses produce cytokines that favour humoral immunity In tuberculoid leprosy M.leprae grows in macrophage vesicles Th1 response little antibody produced but macrophage activation prevents spread of infection and patient usually survives If Th2 response induced antibodies produced can not reach the intracellular pathogen Patient develops lepromatous leprosy