L13: CD4 I Flashcards
what are the tertiary lymphoid organs?
rest of your body / peripheral tissue
What is a CD4+ T cell?
- Part of the adaptive immune response.
- Express CD3 as part of their antigen recognition receptor (they are T cells)
and CD4 (they are T-helper) in their surface. - Orchestrators of the adaptive immune response. 3 main functions:
- Secrete cytokines.
- Interact with B cells to produce antibodies.
- Regulate the immune response.
Life course of a CD4+ T cell
Naive t cell from thymus to secondary lymphoid orgrans. In priming they activate, clonally expand and differentiate. Become effector t cell. Clonal contraction and differentiation occur. In the secondary immune response memory cells are rapidly priming. Activate, clonal expansion (differentiation)
Clonal i.e: a cell brings about daughter cells
CD4+ T cell activation
naïve cells
Tcrs are selected by affinity.
1. CD4+ T cells develop in the thymus - naïve CD4+ T cells
2. They migrate through the blood to SLOs
- If Ag is NOT recognised – circulation
- If Ag is recognised – activation
Encounter
with
dendritic
cell (Ag)
Blood
Lymph
Naïve cells have little functional capacity,
low metabolic rate and they do not divide.
E.g: lymph node. Molecular info by antigen captured by dendiritc cell to migrate here and tcr will recognise with mhc.
Migration through SLOs?
Migration through SLOs is controlled by chemokines, L-selectin
and integrins.
Circulating lymphocyte enters a high endothelial venule in lymph node
Binding of L-selectin (CD62L) on t cell to GlyCAM-1 and CD34 ( ligands on endothelial cells) allows rolling interaction
LFA-1 (integrin on t cells) is activated by CCR7 (a chemokine receptor on t cells) signalling in response to CCL21 or CCL19 (chemokines bound to endothelial surface)
Activated LFA-1 binds tightly to ICAM-1
(anchoring)
Lymphocyte crosses the endothelium and enters lymph node via diapedesis
CD4+ T cell activation: effector cells
- Ag is presented by Dendritic cells (DCs)
- The nature of the Ag -> the signals that the DC provide
-> the type of effector response.
DC provides 3 signals required for CD4+ T cell activation
Dendritic cells are the only ones that can activate naive t cells.
signals?
1st signal: mhc and tcr interaction for activation.
Apc presents cd80/cd86 (B7). the amount of b7 presented by the apc is related to the amount of antigen. More antigen= more b7 recognised by cd28 which mostly signals cell survival. Now cd4 t cell will go into periphery and proliferates.
Signal 1 without signal 2 = anergy
Signal 3: cytokines drive differentiation
Upon correct signalling from a DC, CD4+
T cells activate:
- Proliferation
- Survival
- Metabolic reprogramming (IM lecture)
- Differentiation
factors for effector responses?
Proliferation: expression of IL-2
receptor (high affinity – CD25)
- Survival: expression of survival factors
(Bcl-2)
timeline of action?
1st. Pro inf transcription factors nfat, ap-1, nf-kb first
Then metabolic reprogramming by akt-mtor signalling
Then expressing specific cytokines: il-2 (growth factor for t cells), cd69 (keep them in lymph node), il-2Ralpha (receptor aka cd25)
Then cell division
elimination of antigen?
Elimination of the antigen
In time this will take a week from local infection (penetration of epithelium) t local infection of tissues to lymphatic spread to the adaptive immune response. (inflammatory response)
CD4+ T cell activation: contraction: required as producing x10^7 cells all the time would mean there would be little space for more.
controlling clonal expansion?
Control of clonal expansion
- Effector cell proliferation needs to be controlled
- Upon activation, CD4+ T cells also express co-inhibitory
receptors: CTLA-4
Reostat for Ag levels:
- B7 expression in APC depends
on Ag concentration
- CTLA-4 affinity for B7»_space;> CD28
Cdtla-4 has lots more affinity for B7 so CD28 unable to bind and delivers a negative signal and send the cell to cell cycle arrest.
If the number of B7 molecules on the surface on the APC is low then CTLA-4 sends the negative signal.
CTLA-4 is an immune checkpoint receptor expressed on activated T cells.
It competes with CD28 for binding to B7 molecules.
CD28 provides a co-stimulatory signal for T cell activation.
CTLA-4, however, delivers an inhibitory signal, dampening T cell activation.
The ability of CTLA-4 to inhibit T cell responses under conditions of low B7 expression is crucial for maintaining immune homeostasis and preventing overactivation, especially in scenarios like chronic inflammation or autoimmunity.
However, it can also be exploited by tumors to suppress anti-tumor immunity, which is why CTLA-4 inhibitors (e.g., ipilimumab) are used in cancer immunotherapy.
This is dependent on level of antigen
Clonal contraction: 90-95% effector
cells die. The surviving cells will form
the memory population
CD4+ T cell activation: memory
Memory CD4+ T cells:
* Are selected on high affinity for pathogen (tcr has already been selected)
* Can persist (for long time) in the absence of antigen
* Have increased clonal precursor frequencies
* Have different recirculation patterns
* Do not divide (or little), but rapid differentiation into
effector upon Ag encounter
* Origin: linear and/or asymmetric division
how do memory cells have a long half-life?
Specific pro-survival cytokines (IL-7 -> Bcl2) bcl2 activated through il-7
- Altered metabolic reprogramming (IM lecture)
Memory CD4+ T cells: surveillance
- Central (Tcm) survey peripheral lymphoid tissue - blood
- Effector (Tem) reside in blood and are recruited to inflamed tissue
- Tissue resident (Trm) reside in tissue
Central memory cells (Tcm)
Central memory cells (Tcm) survey peripheral lymphoid
tissue - blood as u can get blood infection so need memory pool that surveys your lymphatic system.
- Express CD62L and CCR7 - same molecules naive t cells express to get into lymph node.
- Low threshold of TCR activation
- Rapid CD40L upregulation
- Slower cytokine responses (compared to other memory
subsets)
Blood
Lymph
Secondary
lymph
organs
Peripheral
tissue
Central memory
