Immunology BE433 Lecture 7 - T cell-mediated immunity PDF

Immunology BE433 Prof Christine Loscher Lecture 7 T cell-mediated Immunity Dendritic cell Co-stim Co-stim Peptide:MHC TCR Macrophage Naïve T cell B cell Effector T cell The initial interaction of T cells with APC also mediated by adhesion molecules Interaction with APC • Interaction bet...

Immunology BE433 Prof Christine Loscher Lecture 7 T cell-mediated Immunity Dendritic cell Co-stim Co-stim Peptide:MHC TCR Macrophage Naïve T cell B cell Effector T cell The initial interaction of T cells with APC also mediated by adhesion molecules Interaction with APC • Interaction between T cell and APC is transient • Interaction stabilised by specific antigen recognition • Causes conformational change in LFA-1 to increase affinity • This interaction can persist for a number of days Figure 8-10 T cell activation • T cells activated by TCR binding peptide:MHC complex and CD4 or CD8 co-receptors • For proliferation and differentiation into armed effector T cells need co-stimulatory molecules • CD8 needs stronger co-stimulation and their clonal expansion is aided by CD4 cells interacting with the same APC • Activated T cells produce IL-2 – growth factor for proliferation and differentiation • Antigen recognition in the absence of co-stim inactivates T cells – anergy – ensures tolerance of T cells to self antigens • Armed effector T cells can respond to their specific antigen without co-stimulation B7 Molecules • • • • • • • • B7.1 – CD80 B7.2 – CD86 Members of immunoglobulin family Found exclusively on the surfaces of cells that stimulate Tcell proliferation Expression of B7 induced on APC on detection of infection through receptors of innate immune system (in built control) Receptor for B7 on T cell is CD28 Ligation of CD28 by B7 is essential for clonal expansion of T cells After activation the T cell expresses a number of molecules that contribute to sustaining the co-stimulatory signal Other co-stimulatory molecules • CD40 ligand on T cells binds CD40 on APC • CD40 ligation activates the T cell and signals the APC to express more B7 – sustain the development of T cell response • CTLA-4 on T cells (after activation) can bind to B7 on APC with great affinity – delivers an inhibitory signal to T cell – acts to limit the proliferative response Maturation of dendritic cells Maturation of DC • • • • • • • • Lose ability to pick up anymore antigen Increase expression of MHC Express B7 Increase expression of adhesion molecules – ICAM, DC-SIGN Secrete chemokine CCL18 to attract T cells The signals that activate DC to migrate and mature after taking up antigen are of key importance in determining whether an adaptive immune response will be initiated These signals are a consequence of recognition of pathogens by the innate immune system Generated through direct interaction with pathogen or by stimulation by cytokines Example 1 • LPS from gram negative bacteria binds to TLR4 on APC • Signalling through TLR4 induces expression of B7 and production of TNFa and IL-12 Example 2 • Pathogen is ingested by APC and degraded inside • Bacterial DNA then binds TLR9 which is found intra-cellularly • Activates signalling pathways and leads to production of cytokines (IFN, IL-6, IL-12) • These can augment the expression of costim molecules Dendritic cells • Can present antigen from fungal, bacterial and viral pathogens • They can distinguish between the class of pathogen and therefore initiate the correct type of adaptive immune response – CD8, Th1, Th2 • The differentiation of CD4 cells into Th1 or Th2 will determine whether humoral or cell-mediated immunity will predominate • Activated/mature DC synthesise different effector molecules depending on pathogen which in turn influences the differentaition of the responding T cell Dendritic Cells Bacteria Helminths DC Viruses Yeast T helper cells IL-4 IL-10 Th1 IL-12 Th2 Tr1 IFN-g IL-23 Th17 IL-10, TGF-b IL-17 IL-4