Cell Mediated Immunity & T Cell Function PDF 2025

CELL MEDIATED IMMUNITY & T CELL FUNCTION Dr. Eman Muhammad Majeed CELL-MEDIATED IMMUNITY Cell-mediated immunity is the arm of adaptive immunity that eradicates infections by cell-associated microbes. Cell-mediated immunity has evolved to battle 2 different types of pathogens: ▪ Fa...

CELL MEDIATED IMMUNITY & T CELL FUNCTION Dr. Eman Muhammad Majeed CELL-MEDIATED IMMUNITY Cell-mediated immunity is the arm of adaptive immunity that eradicates infections by cell-associated microbes. Cell-mediated immunity has evolved to battle 2 different types of pathogens: ▪ Facultative intracellular pathogens, which have adapted to living inside of phagocytic cells that are designed to kill them. ▪ Obligate intracellular pathogens, which can’t replicate outside of host cells. Cell-mediated immunity is dictated by the Th1 response and is mediated primarily via macrophages and CD8+ T cells. Cell-mediated immunity: Cell-mediated immunity (CMI) is a specific type of acquired immune response not mediated by antibodies but by sensitized T cells. CMI performs the following immunological functions: 1. It confers immunity in diseases caused by obligate intracellular bacteria (Mycobacterium tuberculosis), viruses (measles), fungi (Histoplasma capsulatum and parasites (Toxoplasma gondii). 2. It participates in immunological surveillance and immunity against cancer. 3. It plays an important role in pathogenesis of delayed hypersensitivity reactions and in pathogenesis of certain autoimmune diseases, such as autoimmune thyroiditis, encephalitis, etc. Th cells—in general— direct all aspects of the immune system The primary mechanism by which Th cells direct all aspects of immunity is the secretion of cytokines. Note: NK cells also have a role in cell mediated immunity. (i.e. is also activated by Th cells by releasing certain cytokines) T-CELL ACTIVATION T cells require three types of signal for full activation: 1. Antigenic peptide presented on an MHC molecule. 2. Costimulatory signals. 3. Signals from specific cytokines. If a cell does not receive a full set of signals, it will not divide and may even become anergic. Molecules such as CD2 and LFA-1 contribute to the adhesion between a T cell and an APC, and enhance activation signals, but costimulation transduced via CD28 is essential for activation. T helper cell lineage cytokine, and transcriptional profile TH1& TH2 Type 1 T helper (Th1) cells produce interferon-gamma, interleukin (IL)- 2, and tumour necrosis factor (TNF), which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses. By contrast, type 2 Th (Th2) cells produce IL-4, IL-5, IL-10, and IL-13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses. Th1 cells mainly develop following infections by intracellular bacteria and some viruses, whereas Th2 cells predominate in response to infestations by gastrointestinal nematodes.  Th1 and Th2 Th1 cells are promoting and Th2 cells are suppressing defense against intracellular microbe so the balance between activation of Th1 and Th2 cells determines the outcomes of many infections. MACROPHAGE-TH CELL INTERACTION The binding of the TCR of the naive Th cell to the MHC class II–peptide complex of the macrophage provides the first signal to the T cell to begin its activation. This provides the antigenic specificity of the response. Costimulatory molecules on macrophage provide the second signal ( most important costimulatory signal is: B7 protein on the APC must interact with CD28 protein on the helper T cell), and cytokines secreted by the macrophage and the activating T cells themselves induce the proliferation (clonal expansion) and differentiation of the T cells into effector cells and memory cells. IL-2 (secreated by activated Th cells) is the most important factor for T cells that stimulates the proliferation of clones of T cells specific to that antigen. MACROPHAGE-TH CELL INTERACTION MACROPHAGES/B CELLS The Th1 response activates both macrophages and B cells via the cytokine IFN-γ. Effector cells of the Th1 subset recognize the antigens of microbes that have been ingested by macrophages. These T cells secrete IFN-γ and express CD40 ligand, which function cooperatively to activate macrophages. Classically activated macrophages produce substances, including nitric oxide and lysosomal enzymes, that kill ingested microbes. Macrophages also produce cytokines that induce inflammation. In addition induces B cells to class switch to produce opsonizing IgG antibodies that can assist the macrophages with phagocytosis. Cell mediated immunity Th cell /macrophage cytokines The production of IL-12 by the macrophage helps to activate the Th cells. Additionally, the T cells provide tumour necrosis factor (TNF)-, IFN-γ, which promotes macrophage activation that also helps to activate Th cells. Together, IL-12 and IFN-γ also help to promote the differentiation of the naïve Th cell into a Th1 cell. IL-2 (secreated by activated Th cells) is the most important factor for T cells that stimulates the proliferation of clones of T cells specific to that antigen. Effector cells leave the secondary lymphoid tissue, enter into circulation, and travel to the site of the infection. Macrophage-Th cell interaction CYTOTOXIC T LYMPHOCYTES (CTLS) CTLs recognize the cell they will ultimately kill by interaction between their TCR and the MHC class I peptide complex on the surface of the target cell. If the cell is infected with an intracellular pathogen or is expressing neoantigens reflective of tumor transformation, some small proportion of those CD8+ T cells generated from the thymus should be capable of binding their TCRs to this MHC class I/non-self-peptide complex. Th1 & CTLS interaction CTLs are capable of differentiation and cloning by themselves in the presence of the appropriate MHC class I non-self peptide complex stimulus, but are much more effective in so doing if they are assisted by signals from Th1 cells. The Th1 cell secretes IL-2, which acts on CD8+ cells to enhance their differentiation and cloning. This occurs via cross priming. Additionally, interferons produced in the area will increase the expression of MHC molecules to make target cells more susceptible to killing. Cross presentation costimulation  How CTLs kill their target cells? CTLs kill their target cells by the delivery of toxic granule contents that induce the apoptosis of the cell to which they attach. This process occurs in 4 phases: 1. Attachment to the target cell (mediated specially by TCR and CD8). 2. Activation (cytoskeletal rearrangement to concentrate granules against attached target cell). 3. Exocytosis of granule contents (perforin and granzymes). 4. Detachment from the target cell.  The death of the target cell may be mediated in distinct fashions: 1) Perforin present in the CTL granules creates pores in the membrane of the target cell through which granzymes (serine proteases) enter the cell, inducing the activation of caspases, which activate the “death domain.” 2) Cytokines such as IFN-γ with TNF-α or TNF-β can induce apoptosis. 3) Furthermore, activated CTLs express a membrane protein called Fas ligand (FasL), which may bind to its complementary structure, Fas, on the target cell. When this occurs, caspases are induced and death results. Resistance to cell mediated immunity Many pathogenic microbes have evolved mechanisms to resist cell- mediated immunity. These mechanisms include: ▪ Inhibiting phagolysosome fusion, escaping from the vesicles of phagocytes. ▪ Inhibiting the assembly of class I MHC–peptide complexes. ▪ Producing inhibitory cytokines or decoy cytokine receptors, and inactivating T cells, thus prematurely terminating T cell responses. Notes The reaction mediated by the Th1 cell via macrophage and CD8+ T cell activation is often referred to as the delayed-type hypersensitivity (DTH) reaction. Although this is the normal response of the body to intracellular pathogens, it is the exact same mechanism of cellular interactions and cytokine production as a hypersensitivity reactions.