BIO444 Exam2 Study Guide

BIO-444 Study Guide

MHC & Antigen Processing:

Two receptors on lymphocytes:

  1. T-cell receptor (TCR) – recognizes peptide fragments presented in the MHC
  2. B-cell receptor (BCR) – antibody bound to the surface

Major histocompatibility complex (MHC):

  • also known as human leukocyte antigens (HLAs)
    • most people have 12 different HLA alleles
    • >14,000 known HLA alleles in the human population
  • any cell with MHC on its surface is an antigen presenting cell (APC)
  • two different classes of MHC proteins:
    • MHC class I
      • found on all nucleated cells
      • peptides are 8 to 10 amino acids long
      • peptide fragments are generated by the proteasome
      • fragments generated from all cellular proteins are displayed
      • recognized by CD8+ T cells – cytotoxic T cells (CTLs)
    • MHC class II
      • found only on professional antigen processing cells (APCs) (and cTECs):
        • macrophages
        • dendritic cells
        • B cells
      • peptides are 10 to 30 amino acids long
      • peptide fragments are generated by digestion of internalized proteins
      • fragments generated from all cellular proteins are displayed
      • recognized by CD4+ T cells – helper T cells

T Cell Receptors (TCRs):

  • made of immunoglobulin (Ig) domains
  • usually made of an α and a β subunit
  • occasionally made of a γ and a δ subunit – known as γδ T cells (poorly understood)
  • form the TCR complex with CD3 to relay signals to the nucleus
  • formed by somatic recombination of the VDJ gene segments
  • mediated by the VDJ recombinase (RAG1 and RAG2)

T Cell Development:

  • T cell maturation occurs in the thymus over 1-3 weeks
  • T cells enter as progenitor T cells (pro T cells)
    • do not express CD4 or CD8 and are double negative (DN)
    • complete first VDJ rearrangement of the β subunit
    • positive selection: to survive, the pre-TCR must recognize MHC class I or II
      • cortical thymic epithelial cells (cTECs) positively select T cells that recognize and interact with MHC molecules on their surface
      • strongly self-reactive T cells are removed
      • prevents the development of autoimmune responses
  • Double positive T cells:
    • surviving T cells complete second VJ rearrangement of the α subunit
    • express a complete TCR
    • express both CD4 and CD8 (double positive T cells)
  • Single positive T cells:
    • T cells whose TCRs recognize class I MHC–peptide complexes keep CD8 and lose CD4
    • T cells that recognize class II MHC–peptide complexes keep CD4 and lose CD8
  • Negative selection: medullary thymic epithelial cells (mTECs)
    • mTECS express all tissue-specific antigens on their surface
    • driven by the transcription factor AIRE (autoimmune regulator)
    • any T cell that strongly recognizes self-antigens dies by apoptosis
    • prevents the development of autoimmune responses

T Cell Activation

Surviving T cells (naïve T cells) leave the thymus and travel to secondary lymphoid organs

  • naïve T cells constantly interact with dendritic cells
  • complete activation requires three signals:
    • signal 1: antigen presentation in MHC
    • signal 2: mainly provided by B7 costimulatory proteins binding to CD28 on the T cell
      • can also be an inhibitory signal
      • e.g. CTLA-4 and PD-1
      • represses further T cell proliferation, and cytokine production once the pathogen has been eliminated
    • signal 3: polarizing cytokines direct T-cell differentiation into different effector cells
  • once activated, the first cytokine to be secreted is IL-2
    • IL-2 is a potent T cell growth factor
    • ensures that a single activated T cell can produce 10,000 daughter cells

T Cell Effector Functions

Cytotoxic T Cells (CTLs):

  • activated CTLs produce cytotoxins
    • perforin
  • forms pores in cell membranes of target cells
    • granzymes (granule enzymes)
      • delivered through the pores created by perforin
      • serine proteases
      • induce apoptosis

T Helper Cells:

  • TH cells produces cytokines that direct and coordinate the immune response
    • TH1 cells:
      • stimulate phagocyte-mediated killing of infected cells
      • signature cytokine is IFN-γ
      • type 1 immunity
    • TH2 cells:
      • activate responses to multicellular organisms, in particular helminths
      • signature cytokines are IL-4, IL-5, and IL-13
      • type 2 immunity
    • TH17 cells:
      • activate responses to extracellular bacterial and fungal infections
      • signature cytokine is IL-17
    • Follicular helper cells (TFH ):
      • activate B cells
      • when a TFH binds to its antigen in a B cell receptor (BCR), this produces potent B cells and T cells, and increases proliferation
      • increases efficiency of antigen presentation over 10,000-fold
    • Regulatory T cells (Treg):
      • limit activities of effector T cells
      • secrete immunosuppressive cytokines, IL-10 and TGF-β
      • suppress IL-2 production
      • have CTLA-4 on their surface – the inhibitory signal 2

Memory T Cells:

A fraction (<5%) of activated T cells differentiates into long-lived memory cells:

    • maintains a pool of lymphocytes ready to respond rapidly if the pathogen returns
    • cytokines such as IL-7 and IL-15, keep memory cells alive and cycling slowly
    • found in lymphoid organs, peripheral tissues, especially mucosa and skin, and in the circulation