T lymphocytes are crucial players in our immune defense. They develop in the thymus, undergoing a rigorous selection process to ensure they can recognize foreign invaders without attacking our own cells. This fine-tuning creates a diverse army of T cells ready to protect us.

T cells come in different flavors, each with a unique role. Helper T cells coordinate immune responses, while cytotoxic T cells directly kill infected cells. Memory T cells stick around after infections, providing long-lasting protection and forming the basis of many vaccines.

T Lymphocyte Development and Maturation

T-cell maturation and selection

• T-cell precursors arise in bone marrow migrate to thymus for maturation process
• In thymic cortex, T-cell precursors undergo VDJ recombination generating unique T-cell receptors (TCRs) for antigen recognition
• Double positive (CD4+CD8+) thymocytes undergo positive selection in cortex
  • Thymocytes with TCRs binding self-MHC molecules with moderate affinity receive survival signals continue maturation
  • Thymocytes with TCRs failing to bind or binding too weakly to self-MHC undergo programmed cell death (apoptosis)
• Positively selected thymocytes migrate to thymic medulla become single positive (CD4+ or CD8+) committed to helper or cytotoxic lineage
• In medulla, thymocytes undergo negative selection eliminating self-reactive T cells
  • Thymocytes with TCRs binding too strongly to self-peptide-MHC complexes are eliminated by apoptosis preventing autoimmunity
  • This process establishes central tolerance to self-antigens prevents autoimmune disorders
• Surviving mature naive T cells exit thymus enter circulation in periphery ready to encounter foreign antigens mount immune responses

Genetic recombination for receptor diversity

• T-cell receptor (TCR) genes composed of variable (V), diversity (D), joining (J) gene segments allowing for immense combinatorial diversity
• During T-cell development, V, D, J gene segments undergo somatic recombination generating unique TCRs
  • V and J segments recombine for TCR $\alpha$ chain (e.g., V$\alpha$-J$\alpha$)
  • V, D, J segments recombine for TCR $\beta$ chain (e.g., V$\beta$-D$\beta$-J$\beta$)
• Recombination activating genes (RAG1 and RAG2) initiate VDJ recombination process by introducing double-strand breaks at recombination signal sequences
• Random nucleotide additions deletions at V-D and D-J junctions (junctional diversity) further increase TCR diversity (e.g., N-nucleotide addition by terminal deoxynucleotidyl transferase)
• Recombined V, D, J segments form hypervariable regions of TCR, which determine antigen specificity by contacting peptide-MHC complex
• Immense combinatorial junctional diversity allows generation of vast TCR repertoire capable of recognizing wide range of antigens (estimated >10^15 unique TCRs)
  • This diversity contributes to antigen specificity, a key feature of adaptive immunity

T Cell Classes and Functions

T cell classes and functions

• CD4+ T helper (Th) cells
  • Recognize peptide antigens presented by MHC class II molecules on antigen-presenting cells (APCs) like dendritic cells macrophages
  • Provide help to B cells CD8+ T cells through cytokine secretion co-stimulatory signals enhancing their activation differentiation
  • Th1 cells: Secrete IFN-$\gamma$ activate macrophages to combat intracellular pathogens (viruses, intracellular bacteria)
  • Th2 cells: Secrete IL-4, IL-5, IL-13 to promote B cell antibody production isotype switching combat extracellular parasites (helminths)
  • Th17 cells: Secrete IL-17 IL-22 to recruit neutrophils combat extracellular bacteria fungi at mucosal surfaces
  • Regulatory T cells (Tregs): Maintain peripheral tolerance prevent autoimmunity by suppressing other T cell responses through IL-10, TGF-$\beta$ secretion
• CD8+ cytotoxic T lymphocytes (CTLs)
  • Recognize peptide antigens presented by MHC class I molecules on infected or malignant cells (virus-infected cells, tumor cells)
  • Directly kill target cells through release of cytotoxic granules containing perforin granzymes inducing apoptosis
  • Secrete IFN-$\gamma$ to inhibit viral replication enhance MHC class I expression on target cells facilitating their recognition elimination
• Memory T cells
  • Long-lived T cells persist after primary infection or vaccination providing rapid enhanced response upon re-exposure to same antigen
  • Can be either CD4+ or CD8+ exhibit increased sensitivity to antigen faster effector functions compared to naive T cells
  • Contribute to long-term protective immunity against pathogens accelerate clearance upon subsequent infections (e.g., measles, varicella)
  • Form the basis of immunological memory, a hallmark of adaptive immunity

Superantigens and T-cell activation

• Superantigens are bacterial or viral proteins that bypass conventional antigen processing presentation activate large numbers of T cells
• Superantigens bind directly to MHC class II molecules on APCs specific V$\beta$ regions of TCRs outside of peptide-binding groove
  • This interaction is independent of TCR antigen specificity allows activation of T cells with diverse TCRs
• Superantigens can activate up to 20% of all T cells, compared to <0.01% for conventional peptide antigens presented by MHC molecules
• Massive polyclonal T-cell activation leads to excessive release of pro-inflammatory cytokines (IFN-$\gamma$, TNF-$\alpha$, IL-2) causing cytokine storm
• Consequences of superantigen-induced T-cell activation include:
  • Systemic inflammatory response syndrome (SIRS) characterized by fever, hypotension, tachycardia, tachypnea
  • Toxic shock syndrome (TSS) caused by TSST-1 producing Staphylococcus aureus strains leading to rash, hypotension, multi-organ failure
  • Organ damage potentially fatal multi-organ failure due to excessive inflammation vascular leak
• Examples of superantigens include:
  • Staphylococcal enterotoxins (e.g., TSST-1, SEA, SEB) associated with food poisoning toxic shock syndrome
  • Streptococcal pyrogenic exotoxins (e.g., SpeA, SpeC) associated with scarlet fever streptococcal toxic shock syndrome

T Cell Activation and Effector Functions

• T cell activation requires recognition of peptide-MHC complexes (signal 1) and co-stimulation (signal 2)
  • Signal 1: TCR binds to peptide-MHC complex on APCs, providing antigen specificity
  • Signal 2: Co-stimulatory molecules (e.g., CD28 on T cells binding to CD80/CD86 on APCs) enhance activation and survival
• Activated T cells undergo clonal expansion and differentiation into effector cells
• Effector T cells mediate cell-mediated immunity through various mechanisms:
  • Direct cytotoxicity (CD8+ T cells)
  • Cytokine production to activate other immune cells
  • Provision of help to B cells for antibody production
• Cytokines play crucial roles in T cell differentiation and effector functions:
  • IL-2: Promotes T cell proliferation and survival
  • IFN-γ: Activates macrophages and enhances antigen presentation
  • IL-4: Promotes Th2 differentiation and B cell class switching
• The major histocompatibility complex (MHC) is essential for T cell recognition of antigens:
  • MHC class I presents peptides to CD8+ T cells
  • MHC class II presents peptides to CD4+ T cells