Cellular+Immune+Response+III_2024_1_Stdver.pdf

Cellular Immune Response III Differentiation and Functions + of CD8 Effector T Cells Felix N. Toka DVM, PhD, DSc. DACVM Professor, Veterinary Immunology & Virology Department of Biomedical Sciences Objectives Define the role of CD8+ T cells in immune response Elimination of viruses by the immune sys...

Cellular Immune Response III Differentiation and Functions + of CD8 Effector T Cells Felix N. Toka DVM, PhD, DSc. DACVM Professor, Veterinary Immunology & Virology Department of Biomedical Sciences Objectives Define the role of CD8+ T cells in immune response Elimination of viruses by the immune system Viruses cannot be destroyed by cells that lack microbicidal mechanisms Viruses cannot be killed if they are in the cytosol where they are inaccessible to killing mechanisms So how does the immune system get rid of viruses? Kill the infected cell !! The main function of CD8+ T cells The function of killing cells with viruses in the cytosol is mediated by CD8+ cytotoxic T lymphocytes (CTLs) Role of T cells in eradicating infections Other functions of CD8+ T cells Eradication of tumors Cytokine production Critical roles in the acute rejection of organ allografts T-cell therapy Differentiation of CD8+ T Cells into Cytotoxic T Lymphocytes Involves acquisition of the machinery to kill target cells, i.e., acquisition of modified lysosomes - granules that contain perforin and granzymes acquisition of the capability to secrete cytokines, mostly IFN-γ Differentiation is controlled by 2 transcription factors, T-bet and oesmodermin Nature of Antigen and Antigen-Presenting Cells for Activation of CD8+ T Cells REMEMBER Cytosol derived antigens can stimulate CD8+ T cells Naïve CD8+ T cells recognize antigen presented by MHC class I molecules on dendritic cells Antigen presentation cont’d internal ororigin Some APCs are not infected by the virus and do not endogenously synthesize viral antigen cause In such a situation the process of cross-presentation is used This process is also used to present tumor antigens Only specialized subsets of APCs can cross-present antigen (e.g., CD8+ DCs) Cross-presentation of antigens to CD8+ T cells. Role of Helper T Cells in CD8+ T cell differentiation Naive CD8+ T cells may require CD4+ T cell help to differentiate into functional CTLs and memory cells if APCs are directly infected by the microbe, CD4+ T cell help may not be critical CD4+ helper T cells may be required for CD8+ T cell responses to latent viral infections, organ transplants, and tumors In weak innate immune reactions CD4+ T cell help is required Mechanisms of CD4+ T cell help to CD8+ CTLs differentiation Role of Cytokines IL-12 and type I IFNs stimulate the differentiation of naive CD8+ T cells into effector CTLs IL-2 promotes proliferation and differentiation of CD8+ T cells into effector CTLs and memory CTLs IL-21 produced by activated CD4+ T cells induces CD8+ T cell memory IL-15 is important for the survival of memory CD8+ T cells Effector Functions of CD8+ Cytotoxic T Cells CD8+ CTLs eliminate intracellular microbes by killing infected cells CD8+ T cells secrete IFN-γ contribute to classical macrophage activation in host defense Stimulates hypersensitivity reactions Role of T cells in eradicating infections Mechanisms of CTL-Mediated Cytotoxicity CTL-mediated killing involves specific recognition of target cells and delivery of proteins that induce cell death The process: antigen recognition activation of the CTLs delivery of the lethal hit that kills the target cells, release of the CTLs Steps in CTL-mediated lysis of target cells Recognition of Antigen and Activation of CTLs To be efficiently recognized by CTLs, target cells must: express class I MHC molecules complexed to a peptide binds to the CD8 co-receptor bind intercellular adhesion molecule 1 (ICAM-1, the principal ligand for the LFA-1 integrin) form an immunological synapse Formation of conjugates between CTLs and a target cell Mechanisms of CTL-Mediated Cytotoxicity cont’d Two killing pathways 1. The major cytotoxic proteins in the granules of CTLs (and NK cells) are granzyme B and perforin Mechanisms of CTL-Mediated Cytotoxicity cont’d 2. CTLs express a membrane protein called Fas ligand (FasL) that binds to the death receptor Fas, which is expressed on many cell types Inhibition of CD8+ T Cell Responses: The Concept of T Cell Exhaustion In some chronic viral infections, the responses of CD8+ T cells are initiated but gradually extinguished - a phenomenon that is called exhaustion Due to: reduced production of IFN-γ increased expression of multiple inhibitory receptors, e.g., PD-1 Examples of chronic viral infections in animals feline viral rhinotracheitis feline calicivirus canine distemper feline leukemia