IMMUNOLOGY

• 1. Cell Activation, Differentiation, and Memory

  The process by which T cells become activated, differentiate into different subsets, and form memory cells
• Two-signal hypothesis


  T cells require antigen presentation as a first signal, and other molecular interactions can provide the second required activation signal
• 1. cell activation


  1. Antigen presentation

  2. Other molecular interactions provide second signal

  3. T cells differentiate into effector forms
• CD8+ T cells


  • Go on to become killer T cells
• CD4+ T cells


  • Differentiate into several different subsets
• Successful T cell–APC interactions

  1. Organize signaling molecules into an immunological synapse

  2. TCR/MHC-peptide complexes and coreceptors centralize in the central supramolecular activating complex (cSMAC)

  3. Adhesion molecules/bound ligands peripherally localize in the peripheral supramolecular activating complex (pSMAC)
• Signal 1


  Antigen-specific TCR engagement
• Signal 2


  Contact with costimulatory ligands
• Signal 3


  Cytokines directing T-cell differentiation into distinct effector cell types
• Positive costimulatory receptors


  • Facilitate activation, e.g. CD28
• Negative costimulatory receptors


  • Help turn activation off, e.g. CTLA-4 and PD-1
• CD28


  44 kDa glycoprotein homodimer expressed on majority of T cells, markedly enhances TCR-induced proliferation and survival, binds to B7-1 (CD80) and B7-2 (CD86) expressed by APCs, generally involved in initial activation events in T cells
• CTLA-4 (CD152)


  Induced within 24 hours after activation, peaks 2–3 days post-stimulation, binds to B7-1/B7-2 (CD80/86) with higher affinity than CD28, but shuts down signaling pathways ("putting the brakes on")
• PD-1 (program death-1, CD279)


  May help to mediate T-cell tolerance in nonlymphoid tissues
• Clonal anergy results if a costimulatory signal is absent, this helps provide tolerance (especially in periphery)
• If only signal 1 is received, the cell is rendered nonresponsive, this might happen if a T cell isn't screened against a peripheral self-antigen during development
• IL-2


  An example of an autocrine type of cytokine response system, T cells produce the cytokine and the receptor for it, binding induces a very strong proliferation signal during activation stages
• 1. cell activation and differentiation

  1. Initial activation signals 1 and 2 induce upregulation of prosurvival genes

  2. Transcription of IL-2 and IL-2R genes

  3. Outcome is activation and robust proliferation

  4. Production of memory and effector clonal cell populations
• Helper T cell subsets

  • Th1
  • Th2
  • Th17
  • Treg (TR1, nTreg, iTreg)
  • Tfh
  • Th9
  • Th22
• Th1 cells


  Differentiation is induced by IL-12, IL-18, and IFN-γ, characterized by strong IFN-γ production which leads to class switching to IgG classes that support phagocytosis and complement fixation, and supports differentiation of antiviral CD8+ killer T cells
• Th2 cells


  Differentiation is promoted by IL-4, characterized by production of IL-4, IL-5, and IL-13 which promote activities of eosinophils against helminths and induce class switching to IgE
• Th1 and Th2 cytokines


  Can achieve cross-regulation, e.g. IFN-γ from Th1 responses inhibits IgG1/IgE class switching, IL-4 from Th2 responses inhibits production of IgG2a, IL-10 from Th2 responses also inhibits Th1 responses
• Th17 cells


  Differentiation is induced by IL-6 and TGF-β, with IL-23 also playing a role, the master regulator RORγt becomes active and differentiates activating T cells into this subset, IL-17A produced is associated with chronic inflammatory and autoimmune responses, IL-17F and IL-22 may play a role in warding off fungal and extracellular bacterial infections
• Treg cells


  Similar in function to natural Treg cells originating in the thymus, arise during activation of T cells in the presence of TGF-β which induces FoxP3 master regulator, iTreg cells secrete IL-10 and TGF-β to downregulate inflammation and suppress other T-cell subsets
• Th17 and Treg differentiation

  TGF-β is a key cytokine for differentiation of both subsets, IL-6 is the "switch" allowing RORγt to dominate and induce Th17 subset differentiation instead of the suppressive iTreg population
• Tfh cells


  Differentiation is induced by IL-6 and IL-21, leads to activation of Bcl-6 master regulator which inhibits T-Bet, GATA3, and RORγt expression, IL-4 and IL-21 are characteristic secreted cytokines which promote B-cell differentiation
• Helper T cells may not be irrevocably committed to a lineage, early in differentiation T helper subpopulations may be able to shift when exposed to different cytokine environments
• Leprosy - tuberculoid form stimulates Th1, lepromatous form stimulates Th2, HIV progression to AIDS possibly influenced by a shift from Th1 to Th2 responses over time, Epstein-Barr virus may reduce Th1 responses allowing survival advantage for the virus
• Naïve, effector, and memory T cells


  Differ in surface protein expression, e.g. CD44, CD62L, CCR7
• Central memory T cells (TCM)


  Reside in/travel between secondary lymphoid tissues, live longer/divide more times than effector memory T cells (TEM), are rapidly reactivated by second antigen exposure, can differentiate into several subset types depending on cytokine environment
• Effector memory T cells (TEM)


  Travel to/between tertiary tissues, contribute better to first-line defenses, shift right back into effector functions on second antigen exposure
• Memory T-cell persistence seems to depend on cytokine input to induce occasional cell divisions, IL-7 and IL-15 appear important to this homeostatic proliferation
• 1. cell activation events are well-defined and understood, but different subsets of helper T cells are more recently characterized and not fully understood as of yet, and memory T-cell production and biology is a much murkier subject area, but one of active research