Lecture 12 - T Cell-Mediated Immunity

Secondary lymphoid organs are sites for

Initiation and amplification of adaptive immune responses

What controls secondary lymphoid organs

TNF-family cytokines

Entry in secondary lymphoid organs

Naive B and T cells enter lymph node via small blood vessels HEVs into T cell zone

HEVs

High endothelial venules - small blood vessels Naive B and T cells use to enter the T-cell zone

B-cell follicies in lymph

Ag recognition and germinal centre formation

T-cell zones in lymph

DC presentation and activation of T cells

What filters blood-borne antigens and brings them to B and T cells in distinct microenvironments

Spleen

What surrounds arterioles

White pulp

White pulp surrounding arterioles is demarcated from red pulp by

Marginal sinus

What does the Marginal zone contain

Marginal zone B cells, non-recirculating and respond rapidly to blood-borne pathogens

From the marginal zone, where do T cells migrate to and B cells

Periarteriolar lymphoid sheaths (PALs) - T-cell zones

B-cell follicles

What chemokines do Fibroblast reticular cells (FRCs) in T-cell zones secrete

CCL19/21

CCL19/21 function

Attract T cells

What chemokine do Follicular dendritic cells (FDCs) concentrated mainly in the follicles secrete

CXCL13

What does CXCL13 do

Attract B cells

What is MALT and what does it do

Mucosa-Associated Lymphoid Tissues, capture ags directly from mucosal surfaces to initiate local immune responses

Example of MALT

Peyer’s patches beneath gut epithelium

Peyer’s patches are overlain by what

Specialized M cells

What do specialized M cells in Peyer’s Patches do

Transport ags directly from the gut lumen to DCs in lymhpoid tissue below

What do Peyer’s patches support

Localized immune responses and generation of IgA-producing plasma cells

Lymph Node, Spleen, MALT: Antigen source

Tissues via lymph

From blood via arterioles → marginal sinus

From mucosal lumen via M cells

Lymph Node, Spleen, MALT: Entry route for lymphocytes

HEVs

Central arteriole → white pulp

Local mucosal vessels

Lymph Node, Spleen, MALT: Organization

B-cell follicles in cortex, T-cell zone in paracortex

B-cell follicles white pulp, T-cell zone PALS, Marginal zone surrounds white pulp

B and T-cell areas beneath follicle-associated epithelium

Lymph Node, Spleen, MALT: Specialized features

Faciliates ag delivery via DCs

Marginal zone B cells, FRCs, FDCs coordinate blood-borne ag capture

M cells transport antigen across epithelium to DCs

Lymph Node, Spleen, MALT: Main function

Initiative adaptive responses to tissue ags

Detect and respond to blood-borne pathogens

Induce mucosal immunity (IgA) and local memory

Lymph Node, Spleen, MALT: Example location

Through body along lymphatic vessels

Upper left abdomen

Gut Peyer’s patches, tonsils, appendix, BALT/NALT

Naive T cell entering lymph nodes: LFA-1 is activated by

CCR7

CCR7 signaling is activated in response to what chemokines bound to endothelial surfaces

CCL21 and CCL19

Which is produced by both FRCs and HEVs: CCL19 or CCL21

CCL21

What combination of selectins and integrins are used by lymphocytes to enter peripheral nodes

L-selectin and LFA-1

What combination of selectins and integrins are used by lymphocytes to enter mucosal sites

LPAM-1 and MAdCAM-1

What selectins and integrins for a naive T cell in HEV

L-selectin, CD34, GlyCAM-1

What selectins and integrins for all T cells in HEV

LFA-1 and ICAM-1

What selectins and integrins for T cells in spleen

LPAM-1 and MAdCAM-1

Naive T cells enter via HEVs guided by

CCR7-CCL19/21

T cells not activated by antigen presented by DCs exit from lymph nodes via cortical sinuses guided by what gradient

S1P gradient

T cells activated due to finding ag are retained, activated, and proliferate for days until exiting as

Effector cells

What happens to nearly all ag-specific T cells within 48 hours if ag exposure

Trapped in draining lymph node at the site of infection

Local inflammation increases what and reduces what, leading to local node swelling

Increases lymphocyte influx, reduces efflux

What happens to T cells during the trapped phase and what do they exit as

Proliferate, exit as effector cells to infection sites

Where are S1P levels high and low and what does this create

High in blood/lymph

Low in lymph nodes

Creating S1P gradient

How do Naive T cells sense S1P gradient to exit the lymph node

S1P receptors

What does an activated T cell expresse to block S1PR1, keeping it in the lymph node to proliferate

CD69

What happens when T cell activation ends

CD69 drops, S1PR1 returns and effector T cell leaves the node

What drug is used to block S1PR1 to prevent lymphocyte exit and used to reduce immune responses like in multiple sclerosis

FTY720

Dendritic cells location and function in presenting antigen to T cells in secondary lymphoid tissues - Starters

Ubiquitous throughout the body

Results in activation of naive T cells

Macrophages location and function in presenting antigen to T cells in secondary lymphoid tissues - Maintainers

Lymphoid tissue, connective tissue, body cavities

Activation of macrophages by effector and memory T cells

B cells location and function in presenting antigen to T cells in secondary lymphoid tissues - Collaborators

Lymphoid tissue, peripheral blood

Results in delivery of help to B cell by Tfh cells

Conventional DC: 1. Antigen capture in tissues - immature DCs use PRRs to sense pathogens, they do what to antigen to become activated

Phagocytose

Conventional DC: 2. Migration to lymph node - Activated DCs upregulate what which guides them towards what made in lymph nodes

Upregulate CCR7, toward CCL19/21

Conventional DC: 2. Migration to lymph node - Reduce antigen uptake and start processing antigen for what

MHC presentation

Conventional DC: 3. Maturation in lymph node - increase MHC and which co-stimulatory molecules

B7

Conventional DC: 3. Maturation in lymph node - When DCs present antigen to naive T cells, what begins

T-cell priming

Priming

First contact that antigen-specific naive T cells have with antigen

Two major classes of DCs

Conventional DCs and Plasmacytoid DCs

2 major subsets of cDCs

cDC1 and cDC2

Where are cDCs most abundant

Non-lympoid tissues and also populate SLOs

Importance of pDCs and what do they secrete

Sentinels of viral infection

Large amounts of type 1 IFNs

What do T cells use for initial contact (loose binding) to scan the DC surface for its specific peptide-MHC complex

LFA-1 integrin to bind ICAM-1 on DC

What does the TCR do when it recognizes its antigen on the MHC

Sends a signal inside the T cell

What happens to LFA-1 integrin when TCR recognizes its antigen on MHC and sends a signal

Changes shape, stronger grip

What bond acts for a stable T cell and DCs interaction, prolonged contact

High affinity lFA-1 and ICAM-1 bond lock the T cell and DC together

Required for full T cell activation and signal integration

T cells touch and go until

They find the right antigen and stick to their matching DC to receive all activation signals

Signals involved in activation of Naïve T cells by APCs: Signal 1

TCR binds antigen peptide:MHC on surface of activated cDCs, tells T cells what to respond to - specificity

Signals involved in activation of Naïve T cells by APCs: Signal 2

Co-stimulation CD28 (on T cell) with B7 (on APC), confirming real infection - permission

Signals involved in activation of Naïve T cells by APCs: Signal 3

Cytokines from APC tells T cells to be helper or effector cell - instruction

What happens if Signal 2 is not present

Anergy - T cell becomes unresponsive

What happens if Signal 3 is not present

Weak or misdirected response

What 3 steps happen after T-cell activation

Clonal expansion, clonal contraction, memory phase

What happens in clonal expansion

T cell recognizes their ag and receive all 3 signals to rapidly proliferate

Each clone is ag-specific

Which typically expand more: CD4 or CD8

CD8

What happens in Clonal Contraction

When pathogen is cleared, most effector T cells die by apoptosis, preventing unnecessary inflammation and autoimmunity

What happens in the memory phase

A small fraction of T cells survive as long-lived memory cells, remain vigilant for future infections

High affinity IL-2 receptors are ____ structures present only on activated T cells

Three-chain structures

Naive T cells affinity to IL-2R

Moderate affinity, can’t respond strongly to IL-2 yet

After activation T cells start making IL-2 and what do they add to the receptor leading to high affinity and responding powerfully

alpha chain (CD25)

Intermediate affinity - Yc and beta

High affinity - Yc and beta and alpha

IL-2 binds receptors on same cell or nearby cells, driving proliferation and clonal expansion, and shape differentiation

Autocrine or paracrine

High affinity IL-2R allows T cell to do what

Respond to its own IL-2, autocrine signaling

DCs provide signal 1 and 2, which trigger

Transcription of the IL-2 gene and the IL-2 receptor alpha chain CD25

What co-stiumulatory signal in the activation phase boosts IL-2 and T cell proliferation

CD28 on T cells binding to B7 on APCs

What does a T cell start expressing after a short time in the regulation phase

CTLA-4

What does the T cell expressing CTLA-4 do

Higher affinity for B7 than CD28 does, outcompetes it so less signals are sent

What are the 2 ways to inhibit and result

1. CTLA-4 removing B7 from APC surface

2. Negative intracellular signals sent to turn off TCR signaling

Resulting in less IL-2, less proliferation, eventual contraction of the response

What happens since effector T cells no longer need co-stimulation

They act immediately once they encounter their antigen

Activated T cells specialize into

Cytotoxic T cells CD8, Helper T cells CD4, regulatory T cells

TH1 do what

Fight intracellular pathogens

TH2 do what

Fight helminths and promote allergy

TH17 do what

Fight extracellular bacteria and fungi

TFH cells do what

Help B cells in germinal centres

Tregs do what

Suppress immune response

Cytotoxic CD8 T cells relation with apoptosis

Induce apoptosis in infected target cells, while sparing neighbouring uninfected cells

Cytotoxic effector proteins released by cytotoxic T cells cause target cell to do what

Cell-destruct via apoptosis, not lysis, avoiding infalmmation

Both apoptotic routes end in what

DNA fragmentation and controlled cell death

Extrinsic pathway: Activated CTLs express what on their surface and what does it bind to on the target cell

FasL

Fas receptors

Extrinsic pathway: Bind of FasL trimerizes Fas receptors on the target-cell membrane, recruiting adaptor protein

FADD

Extrinsic pathway: What does FADD bind and activate and what does that form

Procaspase-8

DISC

Extrinsic pathway: Caspase-8 becomes active and cleaves downstream executioner caspases like

Caspase-3

Extrinsic pathway: Caspase-3 activates what by cleaving what

CAD

I-CAD

Extrinsic pathway: CAD enters the nucleus and cuts DNA, causing the target cell to undergo what

Apoptosis, clean non-inflammatory death