Immunobiology Unit 5 Review: T Cell Development and Activation

Key Concepts and Terminology

• T cells play a central role in the adaptive immune response by recognizing specific antigens and coordinating the immune response
• T cell receptor (TCR) is a heterodimeric protein complex on the surface of T cells that recognizes peptide antigens presented by MHC molecules
• Major histocompatibility complex (MHC) molecules are cell surface proteins that present peptide antigens to T cells
  • MHC class I molecules present antigens to CD8+ T cells
  • MHC class II molecules present antigens to CD4+ T cells
• Positive selection ensures that T cells can recognize self-MHC molecules, while negative selection eliminates T cells that react too strongly to self-antigens
• Antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells, process and present antigens to T cells
• Costimulatory molecules (CD28, CD80, CD86) provide secondary signals necessary for full T cell activation
• Cytokines are signaling molecules secreted by immune cells that regulate the immune response (IL-2, IFN-γ, TNF-α)

T Cell Origins and Development

• T cells originate from hematopoietic stem cells in the bone marrow and migrate to the thymus for maturation
• Notch signaling plays a crucial role in committing lymphoid progenitors to the T cell lineage
• T cell development in the thymus involves multiple stages: double-negative (DN), double-positive (DP), and single-positive (SP) stages
  • DN stages (DN1-DN4) are characterized by the absence of CD4 and CD8 expression and involve TCR gene rearrangement
  • DP stage expresses both CD4 and CD8 and undergoes positive and negative selection
  • SP stage expresses either CD4 or CD8 and represents mature T cells ready to leave the thymus
• TCR gene rearrangement involves the recombination of V, D, and J gene segments to generate a diverse repertoire of TCRs
• Successful TCR gene rearrangement leads to the expression of pre-TCR, which promotes cell survival and proliferation
• Thymic epithelial cells and thymic stromal cells provide essential signals for T cell development and selection

T Cell Selection in the Thymus

• Positive selection ensures that T cells can recognize self-MHC molecules, which is necessary for their survival and function
  • DP thymocytes that bind to self-MHC molecules with moderate affinity receive survival signals and progress to the SP stage
  • Thymocytes that fail to recognize self-MHC undergo apoptosis (death by neglect)
• Negative selection eliminates T cells that react too strongly to self-antigens, preventing autoimmunity
  • DP and SP thymocytes that bind to self-antigens with high affinity are induced to undergo apoptosis (clonal deletion)
  • Some self-reactive T cells may differentiate into regulatory T cells (Tregs) that suppress immune responses
• Aire (autoimmune regulator) gene promotes the expression of tissue-specific antigens in the thymus, facilitating negative selection
• Cortical thymic epithelial cells (cTECs) mediate positive selection, while medullary thymic epithelial cells (mTECs) and dendritic cells mediate negative selection
• The outcome of thymic selection is a diverse repertoire of self-tolerant T cells that can recognize foreign antigens presented by self-MHC molecules

T Cell Receptor Structure and Function

• TCR is a heterodimeric protein complex composed of an α chain and a β chain (or γ and δ chains in a minority of T cells)
• Each TCR chain consists of a variable (V) region, a constant (C) region, and a transmembrane domain
• The V regions of the α and β chains form the antigen-binding site, which interacts with peptide-MHC complexes
• TCR is associated with the CD3 complex, which consists of γ, δ, ε, and ζ chains and mediates signal transduction
• TCR diversity is generated through somatic recombination of V, D (for β and δ chains), and J gene segments, as well as random nucleotide additions and deletions at the junctions
• Co-receptors CD4 and CD8 bind to invariant regions of MHC class II and MHC class I molecules, respectively, and enhance TCR signaling
• TCR signaling involves the activation of Lck, ZAP-70, and downstream signaling pathways (MAPK, NFAT, NF-κB) that lead to T cell activation and effector functions

Antigen Presentation and Recognition

• Antigen-presenting cells (APCs) process and present peptide antigens to T cells in the context of MHC molecules
• Dendritic cells are the most potent APCs and play a crucial role in initiating adaptive immune responses
  • Dendritic cells capture, process, and present antigens from pathogens or infected cells
  • They express high levels of MHC molecules and costimulatory molecules (CD80, CD86) necessary for T cell activation
• Macrophages and B cells also function as APCs, presenting antigens to T cells during the effector phase of the immune response
• MHC class I molecules present peptides derived from intracellular proteins (viral proteins, tumor antigens) to CD8+ T cells
  • Peptides are generated by proteasomal degradation and transported into the endoplasmic reticulum by TAP (transporter associated with antigen processing)
• MHC class II molecules present peptides derived from extracellular proteins (bacterial proteins, toxins) to CD4+ T cells
  • Extracellular proteins are endocytosed, degraded in lysosomes, and loaded onto MHC class II molecules in specialized compartments (MIIC)
• Cross-presentation allows dendritic cells to present extracellular antigens on MHC class I molecules to CD8+ T cells, which is important for anti-tumor and anti-viral responses

T Cell Activation Process

• T cell activation requires three signals: TCR engagement (signal 1), costimulation (signal 2), and cytokine signaling (signal 3)
• Signal 1: TCR recognizes peptide-MHC complexes on APCs, leading to the phosphorylation of ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 complex by Lck
  • Phosphorylated ITAMs recruit and activate ZAP-70, which initiates downstream signaling cascades (MAPK, NFAT, NF-κB)
• Signal 2: Costimulatory molecules (CD28 on T cells, CD80/CD86 on APCs) provide additional signals necessary for full T cell activation and prevent anergy
  • CD28 signaling enhances T cell survival, proliferation, and cytokine production (IL-2)
  • Other costimulatory molecules (ICOS, 4-1BB, OX40) provide additional signals that fine-tune the T cell response
• Signal 3: Cytokines secreted by APCs and other immune cells shape the differentiation and effector functions of activated T cells
  • IL-12 and IFN-γ promote the differentiation of CD4+ T cells into Th1 cells, which mediate cellular immunity against intracellular pathogens
  • IL-4 promotes the differentiation of CD4+ T cells into Th2 cells, which mediate humoral immunity against extracellular pathogens
• Activated T cells undergo clonal expansion, generating a large pool of antigen-specific effector T cells
• Effector T cells migrate to sites of infection or inflammation and exert their effector functions (cytokine secretion, cytotoxicity)

T Cell Subsets and Functions

• CD4+ T cells (helper T cells) orchestrate the adaptive immune response by secreting cytokines and providing help to other immune cells
  • Th1 cells secrete IFN-γ and TNF-α, activating macrophages and promoting cellular immunity against intracellular pathogens (viruses, intracellular bacteria)
  • Th2 cells secrete IL-4, IL-5, and IL-13, promoting humoral immunity against extracellular pathogens (helminths, allergens) and activating eosinophils and mast cells
  • Th17 cells secrete IL-17 and IL-22, promoting neutrophil recruitment and immunity against extracellular bacteria and fungi
  • Follicular helper T (Tfh) cells provide help to B cells in germinal centers, promoting antibody affinity maturation and isotype switching
  • Regulatory T cells (Tregs) suppress immune responses and maintain peripheral tolerance through the secretion of IL-10 and TGF-β and the expression of CTLA-4
• CD8+ T cells (cytotoxic T cells) directly kill infected or malignant cells through the release of cytotoxic granules containing perforin and granzymes
  • Cytotoxic T cells recognize peptides presented by MHC class I molecules on target cells and induce apoptosis
  • They also secrete IFN-γ and TNF-α, which enhance the anti-viral and anti-tumor immune response
• Memory T cells are long-lived cells that persist after the resolution of an infection and provide rapid and enhanced protection upon re-exposure to the same pathogen
  • Central memory T cells (TCM) reside in lymphoid organs and have high proliferative capacity
  • Effector memory T cells (TEM) circulate in peripheral tissues and have immediate effector functions

Clinical Relevance and Disorders

• Autoimmune diseases result from the breakdown of self-tolerance and the activation of self-reactive T cells
  • Examples include type 1 diabetes (T cell-mediated destruction of pancreatic β cells), multiple sclerosis (T cell-mediated damage to the myelin sheath), and rheumatoid arthritis (T cell-mediated inflammation of the joints)
• Immunodeficiencies can arise from defects in T cell development, activation, or function
  • Severe combined immunodeficiency (SCID) is caused by mutations in genes involved in T cell development (IL-2RG, ADA) and leads to a lack of functional T cells and B cells
  • DiGeorge syndrome is caused by a deletion in chromosome 22q11, resulting in thymic hypoplasia and impaired T cell development
• T cell-based immunotherapies harness the power of T cells to fight cancer and infectious diseases
  • Chimeric antigen receptor (CAR) T cell therapy involves genetically modifying patient's T cells to express a CAR that recognizes a tumor antigen, enabling them to target and kill cancer cells
  • Adoptive T cell therapy involves isolating tumor-specific T cells from a patient, expanding them ex vivo, and reinfusing them back into the patient to boost the anti-tumor immune response
• Vaccines rely on the generation of memory T cells (and B cells) to provide long-lasting protection against pathogens
  • Attenuated vaccines (MMR, varicella) contain live, weakened pathogens that stimulate a strong T cell response
  • Subunit vaccines (influenza, HPV) contain specific pathogen-derived proteins that are presented by APCs to T cells, inducing a targeted immune response