Immunity to TB Week 2

After inhalation of MTB, either can happen:

1. Immediate killing of MTB:PPD -ve
2. If a primary complex occurred: PPD +ve

Mechanisms of delayed T-cell response in TB:

1. Delayed migration of dendritic cells from the lungs to the local lymph node in order to sensitize T-cells.
- Immune system in the lungs needs to ensure there’s a balance between restricting pathogen growth and protecting
lung from collateral damage due to inflammation (immune limiting mechanism)
- This can be done through the action of IL-10 secreted by many hematopoietic cells. Functions of IL-10:
1. Suppresses macrophages and DC needed for initiation of immune response against MTB
1. Inhibits migration of DC to a local LNs; therefore no sensitization of T-cells
2. Inhibition of sensitized T-cells to migrate back from the LN to the infection site by inhibiting chemokines
such as CXCL10
3. Inhibition of the activation of Th1 in the local site (by inhibition of IL-12 which is important for Th1
activation)
4. Inhibition of IFN-γ activation of macrophage antimicrobial pathways.

2. Pathogen inhibition of apoptosis: When MTB infected macrophages die, two patterns of death are observed
- Necrosis, cell lysis and spread of MTB
- Apoptosis, cell membrane is intact, MTB is killed within MQ, can’t spread. Mechanism of apoptosis: TNF
binds to TNF-alpha receptor, activation of extrinsic apoptotic pathway, activation of caspase-8 and caspase-3,
apoptosis. Mitochondrial outer membrane permeabilization (unknown mechanism) leads to activation of the
intrinsic apoptotic pathway which leads to caspase-3 activation as well.
- Pathogen inhibition of apoptosis: MTB inhibits TNF-TNF alpha receptor interaction

3. Delay in the onset of detectable T-cell response (initiated after 11 days instead of 3-5, peak after several weeks
instead of 7-8 days)

4. Influence of T-regs and its cytokines (mainly IL-10 and TGF-β).

Release of cytokines by MTB Infection:

- Macrophages and dendritic cells produce the type 1 cytokines: IL-12, IL-18, and others essential for stimulation of
T lymphocytes (stimulate NKC & T cells to produce IFN-gamma).
- Reduced production of type 1 or proinflammatory cytokines may delay or decrease T-cell stimulation and the
initiation of antigen-specific T-cell immunity.
- IFN-gamma promotes expression of chemokines that recruit inflammatory cells to the lungs
- IL-1 & TNF-alpha: activates MQ/DC (auto-induction) + activation of T cells
Type IV Hypersensitivity (delayed hypersensitivity): Granulomatous hypersensitivity:
- A form of type IV hypersensitivity. Results from persistence of intracellular pathogens or particles cells are
unable to kill within MQs
- Chronic T-cell stimulation and release of cytokines
- Epithelioid cells are typical for granulomatous hypersensitivity and are derived from macrophages under chronic
cytokine stimulation. Always secret TNF potentiating the inflammation

Tuberculin Test: if positive, area of firm red swelling 48-72 hours after initiation
Initiation Mechanisms: Injection of tuberculin (PPD)
- 1-2 hours: PPD taken by DC & local T-cells release TNF-alpha, endothelial cells up-regulate E-selectin, causing
recruitment of neutrophils
- 12 hours: ICAM-1 & VCAM-1 on endothelial cells bind LFA-1 (on monocytes) & VLA-4 (on lymphocytes)
leading to their accumulation in the dermis
- 48 hours: peak of activation, expression of MHC-II on keratinocytes
Effector Mechanisms:
- Antigen presented to CD4 T cells, release of cytokines leading to TC activation & proliferation
- Induction of ICAM-1 and MHC-II on keratinocytes & endothelial cells results in their activation and attraction of
more T cells & MQ

Suppression:
- PGE from keratinocytes & MQ inhibit IL-1 & IL-2 production
- Binding of keratinocytes to activated T cells
- Enzymatic & cellular degradation of hapten-carrier complex