T cells and TCR Flashcards
the antigen binding domain of TCR consist of _____
3 CDR loops (complementarity-determining regions) in each alpha and beta chain
CDR1 interacts with MHC
CRD2 interacts with peptide
CRD3 determines specificity of TCR
key difference in how antibodies and TCR binds antigens
TCR ONLY bind antigens + MHC complex (MHC peptide complex)
antibodies can directly bind native antigen
what are the roles of the following T cell surface molecules:
a. CD28
b. CTLA-4
c. LFA-1
d. VLA-4
a. CD28: costimulation, binds APC (B7 on DC)
b. CTLA-4: inhibitory signaling, binds APC (B7 on DC)
c. LFA-1: adhesion, binds ICAM-1 on APC and endothelium
d. VLA-4: adhesion, binds VCAM-1 on endothelium
what do LFA-1 and VLA-4 binds, respectively? both are expressed on T cell surface
LFA-1: binds ICAM-1 on APC and endothelium
VLA-4: binds VCAM-1 on endothelium
both important for adhesion
which immune cells initiate most immune responses
dendritic cells (DC) - ONLY cells that can directly activate [naive] T cells
how does cell surface expression change from an immature to a mature DC?
immature DC (surveillance) - express Fc receptors, mannose receptors
mature DC (activate T cells) - express B7, ICAM-1, IL-12 needed for T cells activation
what 2 signals are needed for T cell activation (costimulation)
- TCR binds antigen-HLA complex
- CD28 on T cell binds B7 on DC
*** note that only naive T cells needs activation from DC and co-stimulation (once they are activated and mature they can function on their own)
what would happen if a novel virus prevented DC cells from expressing B7?
for [naive] T cell activation, 2 signals are needed (costimulation):
1. TCR + antigen-HLA complex
2. CD28 (T cells) + B7 (DC)
so without B7 expression of DC, T cells could not be activated
immunological anergy
immune system is unable to mount a normal immune response against a specific antigen, usually a self-antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen.
after activation, T cell up-regulation expression of ____, which binds B7 on APC to shut down T cell response
CTLA-4: inhibitory signal transduction
**therapeutic potential for treating autoimmunity, as well as enhancing tumor immunity by blocking its function
injecting soluble CTLA-4 and blocking CTLA-4 are both potential therapeutic treatments.
Explain why and how
CTLA-4 is a surface protein on T cells that binds B7 on APC to provide inhibitory signaling (shuts down T cell activity)
injecting soluble CTLA-4 can be therapeutic for treating autoimmunity
blocking CTLA-4 (with a monoclonal antibody) can enhance tumor immunity
what are CD3-epsilon, gamma, and delta important for
CD3 is a T cell transmembrane molecule that is required for signal transduction by TCR complex
have longer intracelular tails than TCR, and contain ITAMs (immunoreceptor tyrosine based activation motif)
what are the steps of early signaling in T cell activation (name the players involved)?
- TCR complex + coreceptors cluster within lipid rafts upon antigen recognition
- LCK (lymphocyte specific protein tyrosine kinase) phosphorylates ITAMs (immunoreceptor tyrosine-based activation motif) on CD3
- ZAP-70 (zeta-chain associated protein) binds phosphorylated tyrosines, and phosphorylates LAT (linker for activation of T cells) adaptor protein
fill in the blank regarding early signaling events in T cell activation:
- TCR complex + coreceptors cluster within ____ upon antigen recognition
- ____ phosphorylates ____ on CD3
- _____ binds phosphorylated tyrosines, and phosphorylates _____adaptor protein
- TCR complex + coreceptors cluster within lipid rafts upon antigen recognition
- LCK (lymphocyte specific protein tyrosine kinase) phosphorylates ITAMs (immunoreceptor tyrosine-based activation motif) on CD3
- ZAP-70 (zeta-chain associated protein) binds phosphorylated tyrosines, and phosphorylates LAT (linker for activation of T cells) adaptor protein
function of T helper 1 vs 2 cells
Th1: activate macrophages via IFNy (gamma)
Th2: activate B cells via IL-4/5/13
**remember that T helper cells are CD4 T cells, so they recognize MHC II (exogenous) on APC
for each of these, state what cytokines they produce, what immune reaction they cause, and what host defense + roles in disease they have:
a. Th1
b. Th2
c. Th17
a. Th1: produce IFNy —> macrophage activation, IgG production. Intracellular microbe defense, involved in autoimmunity and tissue damage associated with chronic infection
b. Th2: produce IL-4/5/13 —> B cell, mast cell, eosinophil activation, IgE production. Parasite defense, involved in allergic reaction
c. Th17: produce IL-17A/F, IL-22 —> neutrophil and monocyte activation. Extracellular bacteria and fungi defense, involved in organ-specific autoimmunity
what type of T helper does this describe?
- produce IFNy
- cause IgG production
- defense against intracelular microbes
Th1:
- produce IFNy —> activate macrophages
- cause IgG production
- defense against intracelular microbes
- involved in autoimmune diseases, tissue damage associated with chronic infection
what type of T helper does this describe?
- produce IL-4, IL-5, IL-13
- cause IgE production
- parasitic defense
- role in allergic diseases
Th2:
- produce IL-4, IL-5, IL-13
- activate B cells, mast cell, eosinophilic
-cause IgE production —> parasitic defense and role in allergies
what type of T helper does this describe?
- produces Il-17A, IL-17F, IL-22
- causes neutrophilic and monocytic inflammation
- defense against fungi
- role in organ-specific autoimmunity
Th17:
- produces IL-17A, IL-17F, IL-22
- causes neutrophilic and monocytic inflammation
- defense against fungi (and extracellular bacteria)
- role in organ-specific autoimmunity
Th17 produces IL-17
key role of Tregs
regulatory T cells maintain tolerance - inhibition of T cell activation and T cell effector function
how does SIV (simian immunodeficiency virus)/ HIV evade the immune system?
SIV mutates amino acids necessary for binding to MHC I, thereby evading CD8 T cells
what are the 2 phases of selection of thymocytes in T cell development?
- positive selection: chooses T cells with useful TCRs (those that bind/interact with self-HLA)
- negative selection: eliminate T cells with self-reactive TCRs (central tolerance)
*remember that central tolerance (removal of self-reactive clones) occurs in thymus (T cells) and bone marrow (B cells)
T cell maturation increases in a gradient in what direction in the thymus?
from cortex —> medulla, increasing T cell maturation
cortex stromal cells involved in positive selection
medulla stromal cells involved in negative selection
where do T cell subsets develop
in the thymus - differentiation and positive/negative selection
can become CD4+, CD8+, Treg, NK cells, etc
how does the CD4+ T cell repertoire change with age
thymic function decreases with age
basically, diversity of T cells is established earlier in life
with age, the repertoire of naive T cells becomes established
later in life, contraction occurs - less diversity
following a bone marrow transplant, the immune cells will have the genotype of the _____, while the epithelial/stromal cells will have the genotype of the _____
hematopoietic cells are killed by chemotherapy or radiation, but not epithelial/stromal cells
so immune cells will have genotype of donor, while epithelial/stromal cells will have genotype of host
T/F: in T cell development, cells begin double negative (CD4-/CD8-) to double positive (CD4+/CD8+) to single positive (CD4+ or CD8+)
TRUE
in the predominant pathway of processing and presentation of viral antigens to CTL:
a. antigen is cleaved into peptides in an endosomal or lysosomal compartment
b. antigen is synthesized in the cytosol of an infected cell
c. peptides derived from the antigen are transported into lysosomes
b. antigen is synthesized in the cytosol of an infected cell
viruses use host machinery to manufacture proteins (antigens)
these are degraded by proteosome
