Characteristics of the Adaptive Response

There are 4 characteristics of the Adaptive Response. Name them.

The 4 characteristics of the Adaptive response are:

1. Specificity
2. Inducibility
3. Diversity
4. Memory

Characteristics of the Adaptive Response

What provides specificity?

Specificity is provided by the TCR
[signal 1 (clonal selection)]

Characteristics of the Adaptive Response

______ is when a _____ naive T lymphocyte matures (terminal differentiation) after exposure to an ______.

Inducibility is when a preformed naive T lymphocyte matures (terminal differentiation) after exposure to an Ag/Immunogen

Characteristics of the Adaptive Response

• Diversity- an immune response is generated that best protects the host.

• this response is directed by the secretion of specific _____ in response to the type of ______ or trauma

• type of ___signals allows the ___ response to respond to the type of infection/disease

• this response is directed by the secretion of specific cytokines in response to the type of infectious agent or trauma

• type of induction signals allows the adaptive response to respond to the type of infection/disease

Characteristics of the Adaptive Response - Diversity

• ___ is primarily Cell mediated against _____ pathogens, transformed cells

• ___ is primarily ____ against ___ pathogens

SM impt

• Th1 is primarily Cell mediated against intracellular pathogens, transformed cells

• Th2 is primarily Humoral against extracellular pathogens

• Note: all the Th considered CD4⁺

Characteristics of the Adaptive Response

• ____ is increased number of Ag specific cells primed to response upon ___ exposure to the ____ Ag

• To what does this contribute?

• About what cells are we talking?

• Memory is increased number of Ag specific cells primed to response upon 2nd exposure to the specific Ag

• This contributes to: Faster response on second exposure

• Memory cells are G₀ & will expand when stimulated

T cell activation

Step 1

• ____ cells, a type of APC, take up bacterial Ags in the skin & then move to enter a draining lymphatic vessel

• Dendritic cells, a type of APC, take up bacterial Ags in the skin & then move to enter a draining lymphatic vessel

T cell activation

Step 2

• Dendritic cells bearing Ag enter the draining lymph node, where they settle in the ___ areas (Bonus: name the specific area)

• Dendritic cells bearing Ag enter the draining lymph node, where they settle in the T-cell areas (Bonus: name the specific area - paracortex)

T cell activation

Step 3

• Naive T cells can enter lymph nodes in the ___ lymph as well as from the ____

• ___ enter a lymph node across ____ in the cortex.

• Naive T cells can enter lymph nodes in the afferent lymph as well as from the blood

• T cells enter a lymph node across high endothelial venules in the cortex.

T cell activation

Step 4

• T cells monitor Ag presented by ____ & ____

• Binding of ___ (on the T cell) to GlyCAM-1 & ___ (on ECM) allows rolling interaction

• T cells monitor Ag presented by macrophages & dendritic cells

• Binding of L-selectin (on the T cell) to GlyCAM-1 & CD34 (on ECM) allows rolling interaction

• Note: T cells check out APCs by adhesion mlcs, i.e., causes "rollover" of each, "loose binding"

T cell activation

Step 5

• T cells that do not encounter specific Ag leave the node in the ____ lymph

• T cells that do not encounter specific Ag leave the node in the efferent lymph

• Note: T cells already have a recirculation pattern of coming to lymph nodes whether it's going to see Ag or not

T cell activation

Step 6

• T cells that encounter specific Ag proliferate & ____ to ____ cells

• ___ (on T cell) is activated by chemokines bound to ECM 

• Activated LFA-1 binds tightly to ___

• ____ lymphocyte leaves blood & enters lymph node

• T cells that encounter specific Ag proliferate & differentiate to effector cells

• LFA-1 (on T cell) is activated by chemokines bound to ECM

• Activated LFA-1 binds tightly to ICAM-1

• Diapedesis lymphocyte leaves blood & enters lymph node

• Note: DC →combo of MHC & peptide see if the T cell will stick to the DC for a long period of time "tight binding" event.

Co-stimulatory & accessory mlcs

1. CD28 on T cell binds __ , __ on APCs (constitutive)
2. ___ (pan T cell) binds LFA-3 (APC)
3. LFA-1 binds ___
4. ___ - signal transduction
5. ___ induced on T cell binds CD86, CD80 (downregulatory)
6. CD40L induced on T cells binds ___ on __ cells, macrophages
7. ICAM-3 on T cell binds to ___ (APC)

1. CD28 on T cell binds CD86, CD80  on APCs (constitutive) [Note: 2nd signal in activation , necessary for IL-2 production]
2. CD2 (pan T cell) binds LFA-3 (APC) [Note: cell-cell adhesion, activation]
3. LFA-1 binds ICAM-1 (Note: cell-cell adhesion; also binds ICAM-2, pic shows it on T cell, inside-out binding)
4. CD45 (T-cell) - signal transduction  binds CD22 (APC) (Note: Phosphatase in cytoplasmic domain)
5. CTLA-4 induced on T cell binds (co-stimulatory mlcs) CD86, CD80 (downregulatory)
6. CD40L induced on T cells binds CD40 on B cells, macrophages (Note: CD40L also helps CD8⁺ bud doesn't require binding event)
7. ICAM-3 on T cell binds to DC-SIGN (APC) [from pic]

T cell surveillance

1. T cells bind ___ adhesion mlcs
2. If they do not bind/recognize specific ___, they detach & move to next ___
3. Upon ___ engagement, LFA-1 is induced to bind w/ higher ___

1. T cells bind APC adhesion mlcs
2. If they do not bind/recognize specific Ag/MHC, they detach & move to next APC [SM impt]
3. Upon TCR engagement, LFA-1 is induced to bind w/ higher affinity

Conversion of LFA-1 to high affinity

1. T cell initially binds DC via ____ LFA-1 : ICAM-1 interactions
2. Subsequent binding of TCRs sends signal to ___
3. Conformational Δ in LFA-1 ↑ affinity & prolongs _____

1. T cell initially binds DC via low-affinity LFA-1 : ICAM-1 interactions (Note: adhesion mlcs stick out further (others are shorter), "loose binding"; low Ab affinity is 10⁵, T cell is 10⁴)
2. Subsequent binding of TCRs sends signal to LFA-1 (Note: signal recognition event caused this "tight binding" requires hours of contact)
3. Conformational Δ in LFA-1 ↑ affinity & prolongs cell-cell contact

• Note: CD4,TCR & LFA-1 on T-cell; ICAM-1 & MHC class II w/Ag on DC (could be CD8 & class I)

• Professional APCs have MHC ___ & ____

• What does the MHC expression look like on the APCs?

• What does the co-stimulator delivery look like?

• Professional APCs have MHC class I & II & CD80/CD86

• MHC expression:
• DC - low on tissue DCs, high on DCs in lymphoid tissues
• Macs - inducible by bacteria & cytokines - to +++
• B cells - constitutive ↑ on activation +++ to ++++

• Co-stimulator delivery:
• DCs - constitutive by mature, nonphagolytic lymphoid DCs ++++
• Macs & B cells - inducible - to +++

Steps in Adaptive T cell Mediated Immune Response

Recognition Phase

• ____ binding of APC by an Ag specific T cell, primarily in peripheral lymph organs

• Signal 1 - APCs present peptide-MHC (Ag/MHC) to ___ on ____ (Th cells)
• TCR-__
• T cell - CD8 or CD_
• APC - Ag/MHC _ or Ag/MHC II

• Signal 2 - APCs present co-stimulatory mlcs to ___ on T cell leading to ___ production & IL-2R expression
• T cell - CD28
• APC - ___, ___ (CD80/86) [look for IL-1, IL-α

• Clonal selection binding of APC by an Ag specific T cell, primarily in peripheral lymph organs

• Signal 1 - APCs present peptide-MHC (Ag/MHC) to TCR on CD4⁺ T cells (Th cells) (G₀ → G₁ (SM)) [Note: specificity should trump everything, selective about activation = tight binding]
• TCR-CD3
• CD8 or CD4
• Ag/MHC I or Ag/MHC II
• (note: give us time to look for co-stimulatory mlcs)

• Signal 2 - APCs present co-stimulatory mlcs to CD28 on T cell leading to IL-2 production & IL-2R expression (G₁ → S (SM))
• T cell - CD28
• APC - B7-1, B7-2 (CD80/86) [look for IL-1, IL-α]

Steps in Adaptive T cell Mediated Immune Response

Activation Phase

• _____ - T cells are now receptive to autocrine (CD4⁺ T) & paracrine (CD8⁺ T) growth factors (IL-2, IL-4) leading to proliferation

• Clonal expansion - T cells are now receptive to autocrine (CD4⁺ T) & paracrine (CD8⁺ T) growth factors (IL-2, IL-4) leading to proliferation 

Steps in Adaptive T cell Mediated Immune Response

Activation Phase cont'd

• ____ T cells respond to cytokines (ILs) to become effector and/or ____ T cells

• Differentiation - T cells respond to cytokines (ILs) to become effector and/or memory T cells

Steps in Adaptive T cell Mediated Immune Response

Effector Phase

• Macrophage ____ (CD4)
• B cell activation ___ production (CD4)
• Inflammation
• ___ T cell (CD4 or CD8)
• T cell mediated ___

• Macrophage activation (CD4)
• B cell activation, Ab production (CD4)
• Inflammation
• memory T cell (CD4 or CD8)
• T cell mediated cytolysis

Note: T cells want to act on cells not just hand out cytokines

Outcomes of Signal 1 + 2, 1 alone, 2 alone

1. Which one causes the T cell to become anergic?
2. Which one activates the T cell?
3. Which one has no effect on the T cell?

1. Anergy - Specific signal (1) alone [Note: even if cell @ 2nd time had co-stimulatory mlcs]
2. Activates - Specific & co-stimulatory signal (1 + 2)
3. No effect - Co-stimulatory signal alone

2 signal model of T cell activation

1. Phagocytosis & breakdown of bacteria by ____ induces expression of MHC class II & __
2. Macrophage delivers a ____ signal to T cells recognizing bacterial ____ ____
3. Proliferation & differentiation of ___ specific for bacterial protein

1. Phagocytosis & breakdown of bacteria by macrophage induces expression of MHC class II & B7
2. Macrophage delivers a co-stimulatory signal to T cells recognizing bacterial peptide antigen
3. Proliferation & differentiation of T-cells specific for bacterial protein

Immunological Synapse

• T cell interacts w/ the APC to create a tight jxn (pep-MHC migrates from outside to inside)
• At the jxn you have a "bulls-eye" like area with the c-SMAC (enriched by TCRs) in the middle & p-SMAC (a ring of adhesion mlcs) surrounding it
• What mlcs are found in the c-SMAC?
• What mlcs are found in the p-SMAC?

c-SMAC

• TCR
• CD2
• CD4
• CD8
• CD28 - signal 2
• PKC-θ - will become activated

p-SMAC

• LFA-1
• ICAM-1
• talin

ITAM phosphorylation

1. In the resting T cell ___ are not phosphorylated
2. Binding of MHC ligand to the ___ leads to phosphorylation of the ITAMs by _____
3. When the co-receptor binds to the MHC ligand ___ binds to phosphorylated ___ ITAMs & is phosphorylated & activated by ___

On APC: MHC class II

On T cell: TCR, CD4, Lck, Fyn, ZAP-70, ITAMs

1. In the resting T cell ITAMs are not phosphorylated
2. Binding of MHC ligand to the TCR leads to phosphorylation of the ITAMs (CD3) by receptor associated kinases (Src family kinases, eg. Lck & Fyn)
3. When the co-receptor binds to the MHC ligand ZAP-70 (kinase not Src, need to get from cytoplasm to cell membrane) binds to phosphorylated ζ-chain ITAMs & is phosphorylated & activated by Lck (CD4 or CD8)

Note: mutation in ZAP-70 (genotype), person is CD8 deficient (phenotype)

Big picture: Naive T cell recognition of specific Ag presented by a DC initiates pathways of signal transduction that lead to clonal expansion & differentiation

1. Naive T cell interacts w/ DC presenting its specific Ag
2. Activation of the kinase ZAP-70 initiates a series of rxns leading to the activation of PLC-γ
3. PLC-γ cleaves PIP₂ to DAG & IP₃
4. DAG → PKC-θ → tranx factor NF-κβ
5. DAG also → RasGRP → MAPK → Fos (component of AP-1 tranx factor)
6. IP₃ → ↑ Ca²⁺ → calcineurin → tranx factor NFAT (also true for B cells)
7. NF-κβ, NFAT & AP-1 Δ the pattern of gene expression
8. Cell division, proliferation & differentiation  to effector T cells

Signal 2

1. Naive T cells express the low-affinity IL-2R (β,γ chains) bind IL-2 w/ moderate affinity
2. Activated T cells express the high affinity IL-2R (α,β,γ) & secrete IL-2
3. Binding of IL-2 to the IL-2Rα sends a signal to the T cell
4. The signal sent from the IL-2Rα induces T cell proliferation

Key points:

1. Signal 2 induces expression of IL-2 & IL-2Rα (IL-2Rα = CD25)
2. IL-2R composed of γ, β
3. w/o signal 2 = anergy
4. CD8 would put IL-2Rα but not IL-2; would get IL-2 from CD4 (paracrine)
5. CD4 cell would get high affinity receptor & IL-2 (autocrine)
6. CD25 - need FoxP3 as addt'l marker to distinguish Tregs from everday activated CD4

Mechanisms of T cell activation

Normal

Foreign Ag

• recognition results in activation of ≈ 1/100,000  T cells

Exceptional

Allogenic MHC

• foreign MHC recognition → activation of ≈ 1% of T cells [note: a lot of T cells will recognize foreign MHC @ the start]

Exception

Superantigens

•  bacterial exotoxins - mimic specific Ag & cause T cells to divide & differentiate into effector T cells
• circumvent specificity of TCR
• bind simultaneously to MHC class II & TCR (in absence of specific peptide Ag - form a bridge)
• Bind & cross-link MHC class II
• bind to CRR1 & CDR2 loops of Vβ domain of TCR
• superAg stimulation → of up to 20% of CD4 T cells (bind to sites shared by many TCRs → massive polyclonal response)

note: bringing together MHC w/ TCR, thinks it got activated, not processed & presented, only on surface

Exceptional

mitogens

Polyclonal (in vitro stimulation = diagnostic test for T cell fxnality)

• PHA (CD2), ConA (plant-lectin mitogens; T cell only) [note: LPS is for B cells only]
• lectins are 4 subunits used for cross-linking; recognize Mannose -OH
• Anti-CD3 + anti-CD28 mAbs (T cells think they are activated)

note: no receptor stimulus req'd i.e. do NOT act via TCR or Ig

Pts w/ T cells want to know if they are fxnal need to get proliferation - anergized T cells do not proliferate

Allogeneic MHC

• convential recognition of Ag/MHC w/ TCR is full contact (both Ag & MHC)
• Proposed extremes of allorecognition 1. MHC only (very high affinity binding, enough to activate) 2. Ag only (due to polymorphism of MHC mlc dif peptide will be bound (same protein)
• accidental recognition of allogeneic has to do w/ fact that MHC types look alike, existence of allogeneic is unknown to T cell as it's being educated

• if self MHC I → see foreign MHC I, CD8
• if self MHC II see foreign MHC II, CD4
• see the same HLA specific as well
• TCR carefully selected to recognize a self MHC (& peptide); same TCR will see a foreign MHC
• cross-reactive recognition: meant from self-MHC used to recognize foreign. Not processed & presented only on surface (intact MHC)

Mitogens

• Anti-CD3 & anti-CD28 activation of T cells
• Immobilized Abs or presence of APCs
• mimic signal 1 & signal 2
• polyclonal activation - all T cells would have CD3 & CD28

PMA & Calcium ionophore - mimics

• artifically activate T cells - mimic intracellular 2nd messengers
• PMA (DAG) (PKC activation, [Ca²⁺]_i ↑) [1st phosphorylation event]
• ionomycin (ionophore insert into membrane, cause Ca²⁺ channel to form, allow for EC Ca²⁺ to enter cell, [2nd event ↑ in IC free Ca²⁺]

Mechanisms of unresponsiveness to self Ags

• Central tolerance - ____ self-reactive ___ that recognize self ___ in the thymus undergo ___ (deletion)
• Peripheral tolerance - ___ self-reactive T lymphocytes that escape ____ & recognize self Ags in peripheral tissues can be inactivated (___), killed (deletion) or _____ (suppressed)
• "Clonal ignorance" - ____ self-reactive lymphocytes do not respond to ____ in non-inflamed settings

• Central tolerance - Immature self-reactive T lymphocytes that recognize self Ags in the thymus undergo negative selection (deletion) [T_regs are here]
• Peripheral tolerance - Mature self-reactive T lymphocytes that escape central tolerance & recognize self Ags in peripheral tissues can be inactivated (anergy), killed (deletion) or regulated (suppressed) [T_regs can be generated from naive, mature T cells & come into periphery]
• "Clonal ignorance" - Mature self-reactive lymphocytes do not respond to self Ag in non-inflamed settings

Downregulatory APC & T cell interactions

• APC & CD4⁺ T cell
• Signal 1 - MHC __ w/ TCR
• Signal 2 - B7 (CD80/86) w/ ___
• downregulatory signal B7 (CD80/86) w/ ___ [inducible]

• APC & CD4⁺ T cell
• Signal 1 - MHC TCR w/ TCR
• Signal 2 - B7 (CD80/86) w/ CD28
• downregulatory signal B7 (CD80/86) w/ CTLA-4 [inducible]

Response against intracellular microbes

• Delayed type hypersensitivity (DTH) Th1
• Cytotoxic T cell response (CTL) CD8
• Antibody Dependent Cell-mediated Cytotoxicity (ADCC) NK

Response again extracellular microbes or soluble foreign Ags [toxic proteins made by bacteria]

• T help for humoral immune response (Th1, Th2)
• ADCC, [picked up by Eosinophils - NK cells won't pick up EC pathogens, has to recognize a cell]

T cell differentiation

Type of effector of response depends on:

• Type of Ag (EC vs. IC)
• Type of APC presenting the Ag determines which cytokines will be produced
• These interactions occur during the induction phase of Ag-depend T cell activation & differentiation

• Don't confuse IC & EC pathogens w/ endo/exogenous pathways
• EC - pathogens like to replicate outside cells
• IC - pathogens come from outside but like to grow inside eg. TB bacteria, viruses (inert have to be in our cells to activate), will be processed & presented by APCs
• CD4⁺/MHC II exogenous pathway, worse situation is not have CD4⁺ T cells

Signal 3 - cytokine microenvironment

• Signal 1 is Specificity (TCR:MHC/Ag)
• Signal 2 is Activation (CD28:B7)
• Signal 3 is Differentiation
• For full division (mitosis) get signal 1 & 2
• LPS binds to TLR4 (binds to B cells)

Signal 3 - Differentiation

• IL-1, IL-6 or IL-12 (cytokines)
  
• Bind to the IL-12R on CD4⁺ T cell
• T cell daughters will bind cytokines & gain differentiation effector fxn

Effector T cell subsets

T cells fxn by making contact w/ other cells & inducing them to Δ

1. CD8 T cell contacts a virus-infected cell, outcome?
2. CD4 T cell + macrophage, outcome?
3. CD4 T cell + B cell, outcome?

1. CD8 T cell + virus-infected cell = dead virus-infected cell
2. CD4 T cell + macrophage = activated macrophage (cytokines present)
3. CD4 T cell + B cell = plasma cell + Abs

Naive CD4 T cell → Proliferating T cell → Immature effector T cell -Th₀ →Th₁, Th₂, Th₁₇, T_reg differentiation is determined by cytokine microenvironment

Th₀ → Th₁ [note: Th₀ is undifferentiated CD4⁺]

• APC producing IFN-γ &  IL-12
• macrophage & B-cell activation
• production of opsonizing Abs such as IgG1 (growth factor req'd for Ig switch)
• Intracellular microbes
• Under ctrl of tranx factor T_bet

Note: APCs have PAMPs - recognize mlc structure that generally we don't have

Th₀ → Th₂

• Extracellular microbes
• IL-4 production (probably by mast cells) [Th₂ respond to IL-4 to make IL-4; + feedback]
• IL-5
• general activation of B cells to make Abs (respond to cytokines)
• Under ctrl tranx factor GATA-3

Differentiation pathways of CD4 T-cells

Need to know the sequence & key cytokines

FoxP3, RORγt, T-bet & GATA-3 are tranx factors impt in deciding which protein will be made

1. T_reg cells: TGF-β → FoxP3 → TGF-β, IL-10  
2. Th₁ cells: IL-12, IFN-γ →T-bet → IL-2, IFN-γ 
3. Th₂ cells: IL-4 → GATA-3 → IL-4, IL-5
4. IL-17 producing T_h cell: IL-23 → IL-23R → RORγt → IL-17 & IL-17F

Note: TGF-β is anti-inflammatory cytokine, this plus IL-10 are down regulatory of inflammatory response

IL-1, IL-6, TNF-α are inflammatory cytokines

1-3 have + feedback loops

T_reg also has CD4⁺, CD25⁺

Th₁  or Th₂ differentiation or polarization

• Th₁: IFN-γ bind to IFN-γR → STAT1 → T_bet → [↑IFNγ, ↑IL-12R, ↓IL-4 (feedback to T_bet)] → [IL-12, IL-12R, STAT 4 →] & Th₁ [IFN-γ stabilized; IL-4 silenced]

• Th₂: IL-4 bind to IL-4R → STAT6 → GATA-3 → [↑IL-4, ↓IFN-γ ↓IL-12R (feedback to GATA-3)] → Th₂ [IL-4 stabilized; IFN-γ silenced]

• IL-17 producing T_h cell: IL-23 → IL-23R → RORγt → IL-17 & IL-17F

•  It takes about a week for this path to occur i.e. from Th₀ → Th₁ or Th₂
• Fate of daughter cells from originally selected Th₀ could choose either pathway
• Once subset made, it remains a stable subset
• T cell response comes up faster w/ memory cells, i.e. it won't take a week to make Th₁ or Th₂
• All 3 start w/ naive CD4⁺ T cell w/ IL-12Rβ1 and signals through CD28 and/or ICOS

Activation of T lymphocytes

1. Ag recognition - APC w/naive CD4⁺ or CD8⁺
2. Activation - IL-2R on T cell w/IL-2 cytokines
3. Clonal expansion
4. Differentiation into effector & memory CD4⁺ & CD8⁺ T cells
5. Effector fxns: CD4 - activation of macrophages, B cells, other cells
6. Effector fxns: CD8 (CTL) - Killing of infected "target cells"; macrophage activation

Note: 1-4 happen in the lymphoid organs & 5-6 happen in peripheral tissues

• IFN-γ, IL-2: need the IL-2 to get the ytolytic mechanism already present in NK cells
• Recognized by MHC I whereas NK match by KIR for MHC I

• Inititation: Ag/MHC, SuperAg, Co-stimulation → naive T cell encounters Ag

• Clonal expansion: IL-2/IL-2R → most activated T cells become effector cells; some activated and/or effector cells become long-lived memory cells
• Contraction: FasL ≈ TNFα; Fas ≈ TNFR (cell that's destined to die) → many effector cells are short-lived & die by apoptosis; cytokines may be req'd for survival; IL-7, IL-15 (long-lived memory)

• Suicide & fratricide
• how effector cells disappear
• anti-apoptotic - stay alive, maintenance factor vs. growth factor
• actually divide

• CD8 T cells [CTLs - cytotoxins, FASL] bind to virus infected cell [FAS] →T cell secretes effector mlcs onto surface of target cell
• cytotoxins: perforin, granzymes, granulysin
• cytokines: IFN-γ, LT

• CD4 T cells: Th₁ cells [cytokines, CD40L] bind to macrophage containing bacteria [CD40, intra-vesicular bacteria]
• cytokines: IFN-γ (impt for IL-2 growth factor), GM-CSF, TNF-α, LT, IL-3

• Th₂ cells: cytokines & CD40L bind to B cell presenting specific Ag [CD40, bacterial toxin]
• cytokines: IL-4 (+ feedback), IL-5 (eosinophil recruitment), IL-10 (anti-inflammatory), IL-13, TGF-β (mast cells & allergies)

• all T cells
• integrin: LFA-1 (α_L & β₂)

• APC
• adhesion mlc: ICAM-1

• activated effector T cells
• integrin: VLA-4 (α₄, β₁)

• activated endothelium
• adhesion mlc: VCAM-1

VLA = very late Ag

Regulatory T cells

• Most are CD4⁺, CD25⁺, Foxp3⁺ (CD3) T_regs
• → most clinically relevant T_regs, oral immuntity - stuff we ingest we're going to be tolerant to
• Regulation is mediated by cytokines
• T_regs downregulate inflammatory response

• Normal response: Ag recognition & T cell response
• APC bind to naive T cell → effector T cells (T cell proliferation & differentiation) w/IFN-γ → activated macrophage

• Suppresion: APC bind to naive T cell → Suppressor (regulatory) T cells → immunosuppressive cytokines →
• IL-10 inhibits fxns of APCs (IL-12 secretion, B7 expression)
• TGF-β inhibits T cell proliferation
• IL-10, TGF-β inhibit macrophage activation

• Suppression of autoreactive T cells by regulatory T cells (T_reg) requires them to interact w/ the same Ag-presenting cell
• T_reg binding same APC as CD4 T cell causes APC not to be a good APC - suppression of self-reactive T cells

• cell-cell interaction event involved w/T_regs
• T_regs to insulin should block T cell recognition of insulin (as foreign) not something else like influenza
• It isn't just 1 peptide for every protein processed & presented; could be identical or different - block humoral & cell-mediated b/c CD4⁺ @ crux of both
• MHC mlcs will have peptides but all dif; self-MHCs some have multiple peptides
• CD8 seeing self in absence of CD4 seeing self is going to go nowhere, don't have IL-2 (growth factor)

CD4⁺ T cells that differentiate into Th₁ cells secrete

• IFN-γ: acts on macrophages to ↑ phagocytosis & killing of microbes in phagolysosomes & on B lymphocytes to stimulate production of IgG Abs that opsonize microbes for phagocytosis
• IL-2 predominant autocrine growth factor made by this subset of T cells & [along w/ IFN-γ can contribute to the differentiation of CD8⁺ T cells to CTLs (SM impt)]
• Lymphotoxin (LT) activates neutrophils

Activated Th₁ cell

• IFN-γ & CD40L → activates macrophages to destroy engulfed bacteria (upregulate IC killing)
• FasL or LT → kills chronically infeced macrophages, releasing bacteria to be destroyed by healthy macrophages
• IL-2 → induces T-cell proliferation, ↑ing the # of effector T cells
• IL-3 + GM-CSF → Induces macrophage differentiation in the bone marrow
• TNF-α + LT → activates endothelium to induce macrophage adhesion & exit from blood vessel (diapedesis) @ site of infection (if too abundant cause a problem)
• CXCL2 → causes macrophages to accumulate @ site of infection (chemotaxis)

Activation of macrophages by CD4⁺ Th₁ cells

• Th₁ cell & infected macrophage come together → T cell [CD40L & IFN-γ] binds to, & activates, macrophage [CD40 & IFN-γR] → killing of intravesicular bacteria

• Partial activation of macrophage → granuloma formation (mycobacteria, multi-nucleated giant cell, epitheloid cell, T cells)
• macrophage has IC bacterium upregulated killing mechanisms but bacteria survive
• indication of macrophages trying to get rid of IC pathogen, encircle it & wall off granuloma
• Immunosuppressed, T cells not variant; things coming out of granuloma e.g. TB reactivation coming from granulomas

Effector fxns of CD4⁺ Th₂ cells

• IL-4 (& IL-13 - SM) → B-cell → (1) neutralizing IgG Abs (EC bacteria, viruses, toxins) & (2) IgE → mast cell degranulation (helminths, allergies)

Note: IgE bound by tissue mast cells encounters Ag binding event, triggers mast cell degranulation

• IL-5 → eosinophil → eosinophil activation (helminths)
• IL-10, IL-4 → activated macrophage → suppression of macrophage activation

Note: bind to bacteria, block toxin = block disease; deal w/parasites

recruiting eosinophils - elaborate toxic substances on surface of worms?

T cell help for B cells

• Ag recognition induces expression of ___ & cytokines by the Th₂ cell, which activates the __

• B-cell proliferation & differentiation to ____

• Ag recognition induces expression of CD40L & cytokines (IL-4, 5, 6) by the Th₂ cell, which activates the B cell

• B-cell proliferation & differentiation to Ab-secreting plasma cells