Module 12: T-Cell Maturation, Activation and Differentiation

thymocytes

progenitor T cells arise from fetal liver and adult bone marrow and migrate to thymus

Pro T cells

no CD markers
double negative cells (DN)
C-kit
CD44
CD25

C-kt

a receptor for stem cell growth factor

CD44

adhesion molecule - homing

CD25

alpha chain for IL-2 receptor

DN1

migration to thymus

DN2

TCR gamma, delta, and beta-chain rearrangement
T-cell lineage commitment

DN3

expression of pre-TCR
beta selection

DN4

proliferation, allelic exclusion of Beta-chain locus, alpha chain locus rearrangement begins;
becomes DP thymocyte

Pre-TCR signals

cell becomes permissive for TCR alpha locus arrangement
stimulates expression of CD4 and CD8 coreceptors
stimulates proliferation
stops additional TCR beta chain locus rearrangements (allelic exclusion)

Positive Slection

immature thymocytes with
receptors that bind weakly to self-MHC
receptors that do not bind to self-MHC
leads to MHC restriction

negative selection

immature thymocytes with
high affinity receptors for self-MHC alone or self antigen presented by self MHC are eliminated
leads to self-tolerance (unresponsiveness to self-entigen)

Same haplotype

TCR recongizes antiged presented on targe cell with ___ ___ as the thymus
Zinkernagel Experiment

Von boehmer experiment

negative selection requires self antigen and self-MHC

Signal 1

interaction of TCR-CD3 with MHC-peptide

Signal 2

subsequent to signal 1, antigen non-specific signal is provided by interaction between CD28 on T cells and B7 family members of receptros on the APC

Signal 3

cytokine signaling

CD28

activation of naive T cells

ICOS

maintenance of activity of differentiated T cells
a feature of T/B cell interactions

CTLA-4

negative regulation of the immune response
maintaining peripheral T-cell tolerance
reducing inflammation
contracting T-cell pool after infection is cleared

PD-1

negative regulation of the imunte response, regulation of T reg differentiation

BLA

megative regulation of the immune response, regulation of T reg differentiation (?)

Leads to activation ot T helper cells

interaction between CD28 on Th cells and CD80/86 (B7) on APC

leads to inhibition of activated T cells

interaction betweed CTLA-4 (CD152) on Th cells and CD80/86 (B7) on APC

CD28

expressed on resting and activated T cells

CTLA-4

expressed on activated T cells
maximum expression evident 2-3 days post-stimulation
role in T cell homeostasis

Ipilimumab

blocks CTLA-4
T cell activation

Clonal anergy

the inability of T cells to respond to peptide-MHC complex

Fixed APC no CD80/86

no interaction of CD28 with CD80/86

Anergic T cell

binds to MHC and Costimulatory receptor but no response

Fab antiCD-28

blocks interaction with CD80/86

crosslinkage bu superantigen

certain bacterial and viral proteins bind to particular Vb-domains of a TCR and alpha-chains of class II MHC molecules
leads to massive activation of the T helper cell population
Secretion of cytokines by activated T helper leads to systemic toxicity

specificity

each superantigen exhibits ___ to particular V beta genes

Exogenous superantigens

soluble antigens secreted by bacteria
exotoxins released by Gram positive bacteria

Endogenous superantigens

cell membrane proteins encoded by infected virus

Peripheral T reg cell

suppressed immune responses → inhibits antitumor response

Th2 cell

combats helminth infection, activates eosinophils → allergy

Th1 cell

combats intracellular pathogens, activates macrophages → tissue inflammation

Th1 polarizing cytokines

IL-2, IFN-gamma, IL-18

Th1 master gene regulators

T-bet

Th1 effector cytokines

IFN-gamma and TNF

IFN-gamma Th1 function

Enhances APC activity

Th2 polarizing cytokines

IL-4

Th2 master gene regulator

GATA-3

Th2 Effector cytokine

IL-4, IL-5, IL-13

TFN Th1 function

Enhances Tc activation
Protects against intracellular pathogens
Involved in delayed type hypersensitivity autoimmunity

IL-4 and IL-5 Th2 function

protects against extracellular pathogens (Particularly IgE responses)

IL-13 Th2 function

involved in allergy

Regulatory T cells

are CD4+ and CD25+
suppress immune system
inhibit experimentally induced inflammatory bowel disease, experimental allergic encephalitis and autoimmune diabetes
suppression is antigen-specific
cell-cell contact is needed

Fas by FasL

expressed in high levels in activated T cells
binding of ___ ___ ___ leads to rapid apoptotic death (activation-induced cell death (AICD))