Immunology Review

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Where do T cells develop?: Thymus, which arises from the endo and ectodermal layers of the 3rd pharyngeal pouch and brachial cleft.

A bone marrow derived lymphoid progenitor cell colonizes at 8 wks gestation.

From birth to adulthood, get 50 million thymocytes each day, only 1 million survive.
TCR Co-receptors: CD4 = helper T cells
CD8 = cytotoxic T cells

Stregthen TCR engagement w/ MHC/peptide complex; reduce amount of MHC:peptide complexes needed for optimal activation of T cells by 100 fold
THC Structure: - a & b chains (bind peptides to MHC) coupled to 3 dimers for signal transduction

- 30,000 TCR/cell
Composition of thymic epithelial cell: - express high density of MHC class I and II associated peptides

- role in positive (cortical epith. cells) and neg. selection (medullary epith. cells)

- chemoattractant production for thymocyte migration
Composition of thymic dendritic cells and macrophages: - mainly found in the medulla

- role in negative selection
Thymic architecture (immature--> mature): (1) subcapsular region = immature CD3-4-8- double neg. thymocytes

(2) cortex = immature CD3+4+8+ double pos. thymocytes

(3) cortico-medullary junction = mature CD4+8- and CD8+4- thymocytes

(4) medulla
Double negative (DN) CD4-CD8-: - 3-5% thymocytes

- 2/3 are triple negative based on TCR expression, can be further divided on CD44 and CD25

- 1/3 are TCR yd+

- TCR b, y, and d rearrangements occur at this stage

- B selection (checkpoint 1) rearranged b chain product pairs with pre a chain to make a functional TCR for survival and maturation signals
Douple positive (DP) CD4+CD8+: - 85-90% total thymocytes

- TCR a rearrangement occurs here

- most have rearranged TCR ab genes and express low levels of mature TCR

- small subset have high levels TCR

- cells that don't recognize self are discarded

- cells that react with self antigens are discarded (Checkpoint #2)

- death by neglect --> 95% apoptosis
Single positive (SP) CD4+CD8- and CD4-8+: - 5-10% thymocytes

- most mature cells with high levels CD3 and TCR ab

- CD4:CD8 ration 2:1

- most SP are functionally mature and destined to leave the thymus
Checkpoint 1: - TCRbeta VDJ gene rearrangement and expression of functional beta-chain protein to make preTCR

- occurs at DN3 stage

- beta chain BEFORE alpha chain

- uses helix-loop-helix (HLH) family of transcription activators and repressors (turn on/off genes)

- uses RAGs (recombination activating genes)

- lack of RAGs can lead to Omenn's, a rare autosomal-recessive SCID disorder where NK cells are normal, but T & B cells are not--fatal w/in first few months

- preTCR forms a nucleation center with CD3 complex that recruits signaling molecules

- need inframe version, otherwise death
RAGs: - recombination activating genes

- join the different segments together

- used for TCRbeta gene rearrangement

- without these, get Omenn's
Omenn's Syndrome: - rare, autosomal recessive SCID disorder affecting B & T cells, but not NK

- one cause is lack of RAGs

- usually fatal w/in first months of life
Double Neg. Stages: Stage 1: CD44+25-

Stage 2: CD44+25+

Stage 3: CD44-25+

Stage 4: CD44-25-
TCRalpha chain rearrangement: - occurs during DP phase

- DP cells die after 3-4 days
preTCR components and signaling: - preAlpha + beta chain

- CD3 (gamma and epsilon subunits)

- signaling is NOT antigen driven (pre-alpha has intrinsic signaling abilities

- zeta dimers

- Zap70 and Lck (signaling)
Lck: - member of the SRC family of tyrosine kinase

- activates Zap70

- primarily expressed in lymphoid cells of developing thymocytes and mature T cells

- associated with plasma membrane due to palmitoylation/myristylation

- non-covalently associates with cytoplasmic domains of CD4 and CD8

- deletion in mice results in profound block in thymocyte development
Zap70: - member of Syk family of tyrosine kinases

- expressed primarily in developing thymocytes and mature T cells, also NK cells

- located in cytosol

- binds to ITAM-P residues of Zeta chains of the CD3 complex

- activated by Lck at specific tyrosine residues

- deficiency is rare, autosomal recessive SCID characterized by absence of CD8+ T cells, presence of CD4+ Tcells that are unresponsive to TCR-mediated stimuli (defective Tcell signaling and abnormal tymic ontogeny)

- genetic deletion --> reduced SP CD4 or CD8 T cells, but normal DN and DP thymocytes
formation of preTCR nucleation center: - results from preTCR associated with epsilon, delta, and gamma chains of the CD3 complex

- recruits several signaling molecules as result of phosphorylation of tyrosine residues contained within immunoreceptor tyrosine based activation motifs (ITAMS)
ITAMS: - immunoreceptor tyrosine based activation motifs

- contain tyrosine residues phosphorylated by the preTCR nucleation center
Chronic Granulomatis Disease: - inherited defect of NADPH oxidase complex

- recurrent infections with catalase positive organisms

- these include: Staphylococcus, Burkholderia cepacia, Nocardia, Mycobacteria, Serratia, Klebsiella, Pseudomonas species

- fungi, esp. Aspergillus and Candida

- recurrent infections lead to lymphadenitis, abscesses and granuloma formation w/in first 2 years of life
Formation of ROS in oxidative burst: (1) O2 -> O-2 (NADPH oxidase)

(2) O2- -> H2O2 (superoxide dismutase)

(3) H2O2 + Cl- -> HOCL (myeloperoxidase- MPO)
Pseudomonas aeruginosa fighting back: modifies phagocytic receptors to prevent phagocytosis
Yersinia virulence factors: disrupts ingestion stage of phagocytosis
Listeria and Shigella virulence factors: escape from phagosome and enter cytosol
M. tuberculosis and Legionella virulence factors: stall phagosome maturation
Salmonella virulence factors: uneffected by lysosomal enzymes
Peroxynitrite formation (reactive nitrogen series): (1) O2 -> O2- (NADPH oxidase)

(2) O2- + NO -> ONOO- (peroxynitrite)
Non-oxidative killing mechs of phagocytes: - proteins w/in granules released when cell is stimulated

- lysozyme (disrupts peptidoglycan), lactoferrin, proteases, defensins (also in Paneth cells in GI) and other cationic proteins
How does phagocytosis of apoptotic bodies not produce inflammation?: TGF-beta secreted (anti-inflammatory)
What does TGF-beta do?: anti-inflammatory
What does somatic recombination mechanism do?: generates a diversity of TCR to recognize diverse pathogens
What does MHC polymorphisms do?: - gives species a large number of alternative MHCs that differ in binding pockets

- this combats pathogenic mutation around a stereotyped defense system
How does clonal selection work in the thymus?: Stage 1: POSITIVELY select clones that recognize self-peptide in an individual's own MHC molecultes

Stage 2: NEGATIVELY select overly self-reactive clones with high affinity for self peptide-MHC complexes

* this allows T cells to bind and recognize pathogen peptides prior to encountering pathogens
What is immunologic self?: set of self-peptides and self-MHC molecules that generates and is recognized by the individual's adaptive T cell repetoire

- TCR repetoire selected on self-peptide-self MHC is nearly unique for each individual
What do you do with a cytosolic virus or pathogen?: - bind it on class I MHC

- present it to CD8 T cells

- Tcells cause death of cell presenting the viral antigen

-
What do you do with an ingested bacteria or endocytotic pathogen?: - bind peptides to MHC class II or I

- present it to CD4 or CD*

- Tcells cause activation of cell to enhance pathogen killing
What do you do with extracellular pathogen or toxin?: - bind peptide to MHC class II

- present it to CD4 Tcells

- Tcells provide help to B cell for production of Abs
What is the structure of MHC class I?: - 3 alpha chains and 1 beta

- alpha chain combines with separate beta2 myoglobin
What is the structure of MHC class II?: - 2 alpha chains and 2 beta

- peptide more exposed than on class I
CD4+ --> Th1: IL-12
IFN-y

(IL-2 autocrine loop after activation)

INHIB: IL-4
CD4+ --> Th2: IL-4

(IL-4 = autocrine loop)

INHIB: IFN-y
Cd4+ --> Th17: IL-17
IL-6
CD4+ --> Treg: TGF-B
IL-10
What does Th1 produce?: IFN-y
TNF-a
IL-2
What does Th2 produce?: IL-4 (induces class switching in B cells)
IL-5
IL-10
IL-13

-> B cell activation
What does Th17?: IL-17
IL-6
What does Treg produce?: TGF-B
IL-10
How are peptides loaded onto Class I MHC?: - MHC Class I molecules noncovalently assoc. w/ B2M in ER
- chaperones displaced as AG presentation occurs
- in cytosol, viral proteins synthesized, chopped up into peptides, transported into ER by TAP, loaded on MHC Class I
WHat does TAP do?: transports viral peptides into ER for loading onto MHC Class I
How are viral proteins degradated in the cytosol?: Targeted for degradation by proteosome
How does T cell stimulate B cell for class switching?: CD40 on B cell makes contact w/ CD40L on T cell
What do you need for CD8 memory cells?: CD4 help
What are the markers for naive T cells?: L-selectin/CD62L: peripheral LN homing

CCR7: chemokine receptor (same as APCs S.T. migrate to same area)

no IL-2R (CD25)
What are the markers for effector T cells?: adhesion molecules (integrins, CD44)

secrete cytokines

CCR5, CXCR4: recognize chemokines secreted by activated cells in periphery

IL-2R (CD25)

FasL

no CD62L (don't stay in LN)
What are the markers of central memory cells?: CD62L: in LN

CCR7

IL-2R: respond to small amounts of IL-2 by proliferation

secrete IL-2

adhesion mols

phenotype similar to naive, but have IL-2R
What are the markers of effector memory cells?: phenotype similar to effector, but don't all have IL-2R

adhesion mols

secrete IL-2

CCR5 & CXCR4

FasL
no CD62L: in periphery

secrete cytokines (IL-5, IFN-y)
What is CCR7?: chemokine receptor that brings naive and central memory cells together in Tcell zone of LN
What is CCR5 and CXCR4?: chemokine receptor recognizing secreted chemokines from activated cells in periphery

on effector and effector memory T cells
What is CD25 and where?: =IL-2R, on effector and central memory T cells
What are some regulatory proteins inhibiting complement activation?: DAF (Decay accelerating factor) = membrane protein disrupting binding of Factor B to C3b or C4b2a to C3b

MCP (membrane cofactor protein)= cofactor for proteolysis of C3b into INACTIVE frags, mediated by plasma enzyme Factor 1

C1 INH = reg protein, stops complement activation early (C1 stage)
What do deficiency in C3 cause?: susceptibility to infections, early fatal
What does deficiency to C2 and C4 (classical) cause?: NON LETHAL

incr. incidence of immune complex dxs resembling SLE
WHat do deficiencies in C9 and MAC cause?: incr. susceptibility to Neisseria
What does deficiency of C1INH cause?: hereditary angioneurotic edema

(excessive C1 activation and production of vasoactive protein frags leading to edema in larynx and other tissues)
WHat does deficiency in enzyme that synthesizes glycolipid anchor for DAF and MCP cause?: paradoxymal nocturnal hemoglobinuria

(uncontrolled complement activation on erythrocytes leading to lysis of erythrocytes)
Which AIDs are class I, CD8 (HLA A, B, C)?: psoriasis
psoriatic arthritis
Reiter's symdrome
ankylosing spondylitis
Which AIDs are class II, CD4 (HLA DR, DQ, DP)?: MS
RA
SLE
Pemphigus vulgaris
What does AIRE deficiency cause?: APECED
WHat does Foxp3 deficiency cause?: IPEX
- Foxp3 used by reg CD4 T cells
I= immune dysregulation (Coombs, anemia)
P= polyendocrinopathy (T1DM)
E= enteropathy (celiac like epithelium)
X= X-linked
What does deficiency in CTLA4 cause?: autoimmune disorders
What does deficiency in Fas?: -failure of apoptosis
- ALPS = autoimmune lymphoproliferative syndrome
- hemolytic anemia, thrombocyopenia
What does gain of function of PTPN22 cause?: autoimmunity
WHat does an increase in memory effector T cells cause?: no need for CD28 stimulation

lower threshold of activation by stress
Pemphigus vulgaris: blistering skin disease affecting skin and cornified epi of esophageous

threapy = immunosuppressive

autoantibodies IgG to desmoglien 3

HLA DRB1*0402 = susceptibility
RA: mapped to specific MHC binding pocket (P4)

susceptibility assoc. w/ DR1, DR4, DR10, DR14

BUT DRB1*0402 (pemphigus vularis) NOT assoc, nor is DRB1*1401

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