IMM: BLOCK 2: WEEK 7 REVIEW

Naive T cell activation

• After negative selection, T cells are mature and leave the thymus
• Both CD4+ and CD8+ T cells require a "first" and "second" signal for activation
• The "first" signal comes from TCR/CD4 and p:MHC class II complex on dendritic cell
• The "second" signal comes from CD28 co-stimulatory receptor & B7 (CD80/86)
• *CD40 & CD40L are key co-stimulatory molecules for CD4+ cells
• *4-1BB & 4-1BBL are key co-stimulatory molecules for CD8+ cells
• CD58 can also stimulate CD8+ T cells if CD28 is missing
• The first signal alone leads to tolerance/anergy
• First + second signal = Activation
• First + second signal + cytokines = Effector function
• If only the first signal is received, the T cell becomes tolerant, or anergic, and cannot be activated.
• The immunological synapse forms between a naive T cell and a dendritic cell
• It includes a central (c-SMAC) and peripheral (p-SMAC) supramolecular activation complex (c-SMAC)
• The c-SMAC mainly contains signaling molecules and the p-SMAC mainly contains adhesion molecules

Signal transduction

• The TCR and CD4 co-receptor bind to the p:MHC class II complex on the dendritic cell, delivering the first signal for T cell activation
• The CD28 co-stimulatory receptor on the T cell binds to the B7 (CD80/86) co-stimulator on the dendritic cell, delivering the second signal for T cell activation
• ITAMs (immunoreceptor tyrosine-based activation motifs) are conserved sequence that are repeated twice in the cytoplasmic tails of the TCR.
• They initiate intracellular immune signaling and activation of immune cells
• IL-2 is a cytokine that drives proliferation and differentiation of activated naive T cells

CD4+ and CD8+ T cell Maturation and Activation

• Both CD4+ and CD8+ T cells mature in the thymus and become single positive during positive selection
• CD4+ cells mature and differentiate into various subsets based on their role with different cytokine production
• The most important subtypes are TH1, TH2, TH17, Treg and Tfh
• CD8+ cells differentiate into cytotoxic T lymphocytes (CTLs)
• Their activation and differentiation depend on antigen presentation and cytokine signaling
• CD8+ cells are able to kill infected cells that present viral or tumor antigens

Immunological synapse

• It is an ordered structure that functions as an immunological synapse
• The immunological synapse is formed when two immune system cells bind with receptors and adhesion molecules
• It allows the exchange of signals and the secretion of effector molecules

Homing & Trafficking

• Homing refers to the process of T cells migrating from the thymus to secondary lymphoid tissues
• Lymphocyte trafficking is the movement of lymphocytes between different tissues
• They are regulated by chemokines, adhesion molecules and homing receptors that are expressed on the surfaces of lymphocytes
• T cells use chemokines to find their way to lymph nodes where they can encounter antigens.
• chemokines are specific for different lymphoid organs, providing precise guidance for homing.

Dendritic cell maturation and antigen presentation

• Dendritic cells act as antigen-presenting cells (APCs)
• They capture antigens and present them to T cells
• Maturation is a process that increases their ability to present antigens
• It involves changes in expression of MHC molecules, co-stimulatory molecules, and chemokine receptors
• During maturation, dendritic cells migrate from the tissues to the lymph nodes, where they can activate T cells

Memory T cells

• They are long-lived T cells that can rapidly respond to a re-exposure to a specific antigen
• They are generated from activated naive T cells during an immune response
• They provide long-term protection against pathogens

Importance and Significance of IL-2

• Interleukin-2 (IL-2) is a crucial cytokine that regulates T cell proliferation, differentiation, and survival
• It is mainly secreted by T cells (CD4+ and CD8+)
• It has different functions depending on the context and the stage of T cell activation
• IL-2 promotes the expansion of antigen-specific T cells
• It contributes to the establishment of memory T cells
• It also contributes to the suppression of immune responses

Central tolerance

• Ensures that T cells do not attack self-antigens or other antigens in the body
• It is established during thymic T cell development
• It is mainly mediated by negative selection
• It prevents the development of autoimmune diseases