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  T helper and cytotoxic T cells, crucial players in adaptive immunity
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  • Responsible for mounting targeted responses against pathogens and aberrant cells
  • Their activation is a multifaceted process involving intricate molecular interactions and signaling cascades within the immune system
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  1. Antigen Processing

  2. Antigen Loading and Presentation

  3. T Cell Receptor (TCR) Recognition

  4. Co-stimulation

  5. Inhibitory Pathways

  6. Signal Transduction and Activation

  7. Gene Expression and Differentiation

  8. Clonal Expansion and Effector Functions

  9. Memory Formation
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  In APCs (dendritic cells, macrophages, and B cells), endocytosed antigens are processed by proteolytic enzymes in specialized cellular compartments
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  • Peptide fragments are loaded onto MHC class I or MHC class II molecules in the endoplasmic reticulum (ER) or endosomal compartments, respectively
  • Genes encoding MHC molecules include HLA-A, HLA-B, and HLA-C (MHC class I) and HLA-DP, HLA-DQ, and HLA-DR (MHC class II)
  • Accessory proteins like TAP (transporter associated with antigen processing) and chaperones (tapasin, calreticulin) assist in the loading of peptides onto MHC class I molecules
  • The peptide-MHC complexes are then transported to the cell surface for recognition by T cells
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  • A heterodimer composed of α and β chains (or γ and δ chains in γδ T cells), encoded by specific gene segments that undergo somatic rearrangement during T cell development
  • Associates with the CD3 complex (CD3γ, CD3δ, CD3ε, and CD3ζ), which is involved in signal transduction upon TCR engagement
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  • CD4 and CD8 co-receptors on T cells interact with MHC class II and MHC class I molecules, respectively, enhancing the binding and signaling of the TCR-antigen-MHC complex
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  • CD28 on T cells interacts with CD80 (B7-1) and CD86 (B7-2) on APCs, providing a critical co-stimulatory signal for T cell activation
  • Additional co-stimulatory molecules, such as ICOS (Inducible T-cell COStimulator) and OX40, can further modulate T cell responses
• Inhibitory Pathways


  • Inhibitory receptors like CTLA-4 (Cytotoxic T-Lymphocyte-Associated protein 4) and PD-1 (Programmed cell Death protein 1) on T cells interact with their ligands (CD80/CD86 and PD-L1/PD-L2, respectively) on APCs to dampen T cell responses and maintain self-tolerance
• Proximal Signaling


  • Upon TCR engagement, the Src family kinases Lck and Fyn become activated and phosphorylate the immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 complex
  • ZAP-70 (Zeta-chain-Associated Protein kinase 70) is recruited and activated, leading to the phosphorylation of downstream adaptor proteins like LAT (Linker for Activation of T cells) and SLP-76 (SH2 domain-containing Leukocyte Protein of 76 kDa)
• Signaling Cascades


  • Phosphorylated LAT and SLP-76 serve as scaffolds for the assembly of signaling complexes, recruiting enzymes like phospholipase C-γ1 (PLCγ1), which generates second messengers like diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3)
  • DAG activates protein kinase C (PKC) isoforms, while IP3 triggers calcium release from the endoplasmic reticulum, leading to the activation of transcription factors like NFAT (Nuclear Factor of Activated T cells), AP-1 (Activator Protein 1), and NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells)
• Gene Expression and Differentiation


  1. Activated transcription factors regulate the expression of genes involved in T cell activation, proliferation, and differentiation, such as IL-2 (Interleukin-2), IFN-γ (Interferon-gamma), and various cytokine receptors

  2. The cytokine microenvironment, including IL-12, IL-4, TGF-β, and IL-6, along with specific transcription factors like T-bet, GATA3, RORγt, and Foxp3, drive the differentiation of naïve CD4+ T cells into distinct effector subsets (TH1, TH2, TH17, and Treg cells, respectively)
• Proliferation and Differentiation


  • Upon activation, T cells upregulate the expression of IL-2 and its receptor (IL-2R), which drives clonal expansion and differentiation into effector cells
  • Transcription factors like c-Myc and E2F regulate cell cycle progression and proliferation
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  • TH cells provide help to B cells for antibody production and modulate other immune responses through the secretion of various cytokines
  • TC cells acquire cytotoxic functions and can directly eliminate infected or abnormal cells through the release of cytotoxic granules containing perforin and granzymes or by inducing apoptosis via the Fas/FasL pathway
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  1. A subset of activated T cells differentiates into long-lived memory T cells (central memory and effector memory), which can rapidly respond to subsequent encounters with the same antigen

  2. Transcription factors like BCL-6, ID3, and TCF-1 play crucial roles in the development and maintenance of memory T cell populations
• The activation of TH and TC cells is a highly regulated process that involves multiple steps, including antigen presentation, TCR engagement, co-stimulation, signal transduction, clonal expansion, and differentiation into effector subsets. These processes ensure that T cell responses are appropriately tailored to the specific pathogen or abnormal cells encountered, leading to effective immune surveillance and clearance of threats.
• TH and TC cells


  Perform distinct roles in the immune response, tailored to combat specific types of pathogens and abnormal cells
• TH cells


  • Characterized by the expression of CD4 co-receptor
  • Play pivotal roles in orchestrating immune responses by secreting cytokines and providing help to other immune cells
• TH1 cells TH2 cells, TH17 cells, Regulatory T Cells (Treg)
• TH1 cells


  • Produce cytokines such as interferon-gamma (IFN-γ) and interleukin-2 (IL-2)
  • Play a crucial role in cell-mediated immunity against intracellular pathogens, particularly viruses and intracellular bacteria
  • Activate macrophages, enhance cytotoxic T cell responses, and promote the differentiation of B cells into antibody-producing plasma cells
• TH2 cells


  • Secrete cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13)
  • Stimulate humoral immunity and eosinophil-mediated responses
  • Important for combating extracellular parasites and allergens, promoting the production of antibodies such as IgE and the activation of eosinophils to expel parasites
• TH17 cells


  • Produce interleukin-17 (IL-17) and other pro-inflammatory cytokines
  • Contribute to the defense against extracellular pathogens, particularly fungi and bacteria at mucosal surfaces
  • Stimulate the production of antimicrobial peptides and recruit neutrophils to sites of infection
• Regulatory T Cells (Treg)


  • Characterized by the expression of Foxp3
  • Crucial for maintaining immune homeostasis and suppressing excessive immune responses to self-antigens and harmless environmental antigens
  • Play a critical role in preventing autoimmune diseases and dampening immune responses after the clearance of pathogens
• TC cells


  • Distinguished by the expression of CD8 co-receptor
  • Specialized in recognizing and eliminating infected or abnormal cells through direct cytotoxic mechanisms
• Cytotoxicity


  1. Activated TC cells differentiate into cytotoxic T lymphocytes (CTLs) capable of recognizing and killing target cells expressing specific antigens

  2. CTLs induce apoptosis in target cells by releasing perforin and granzymes, which trigger caspase-mediated cell death pathways
• Antiviral Defense


  • TC cells play a crucial role in the clearance of virus-infected cells by recognizing viral antigens presented on MHC class I molecules
  • This process prevents the spread of viral infection and contributes to the resolution of viral diseases
• Tumor Immunosurveillance


  • TC cells are involved in immune surveillance against cancer by recognizing and eliminating tumor cells expressing tumor-specific antigens
  • This process helps in controlling the growth and spread of cancerous cells
• Memory Response


  • Following the resolution of an infection, a subset of activated TC cells differentiates into memory T cells, which persist in the body and provide rapid and enhanced immune responses upon re-encountering the same pathogen
  • Memory TC cells contribute to long-term immunity and protection against recurrent infections
• TH and TC cells are essential components of the adaptive immune system, playing complementary roles in orchestrating and executing immune responses against a wide range of pathogens and abnormal cells
• Their activation and differentiation into effector subsets are tightly regulated processes that ensure the appropriate targeting and elimination of threats while maintaining immune homeostasis
• The question of whether one cell type or component of the human immune system is considered more important than others is complex and multifaceted
• Within the scientific community, there isn't a unanimous consensus that prioritizes one specific cell type or component as categorically more important than all others
• The immune system is recognized as a highly integrated network comprising various cells, tissues, and molecules, each playing critical roles in mounting effective immune responses against pathogens, maintaining immune homeostasis, and preventing autoimmune diseases
• Certain cell types and components have garnered significant attention due to their central roles in orchestrating immune responses and their implications in health and disease
• Studying diseases that arise from deficiencies or dysregulation of specific immune components provides valuable insights into their indispensable roles and the underlying biochemical mechanisms involved
• T Cells (TH and TC Cells)

  Central players in adaptive immunity, orchestrating and executing immune responses against pathogens and abnormal cells
• The importance of T cells is underscored by their indispensable roles in combating infections, regulating immune responses, and providing immunological memory
• Severe combined immunodeficiency (SCID)

  A group of inherited disorders characterized by a profound lack of functional T cells, often accompanied by deficiencies in B cells and NK cells
• Without functional T cells, patients with SCID are unable to mount effective adaptive immune responses, leading to recurrent and life-threatening infections
• The success of T cell-based immunotherapies, including checkpoint inhibitors and chimeric antigen receptor (CAR) T cell therapy, in treating cancers highlights the therapeutic potential of T cells in combating diseases