Cell-Mediated Immune Responses Flashcards
Where do intracellular microbes replicate?
In the cytoplasm of host cells where they are protected from microbicidal activities
What do T cell responses require?
Interactions with other cells
What does the TCR mediate?
Signal 1
How does the TCR complex divide the labor of signaling?
The TCR variable region detects antigenic peptide
The presenting MHC molecule directs the T cell response
Conserved CD3 and zeta complexes signal to the T cell
Why is adhesion important in T cell signaling?
T cells respond weakly to antigens
The T cell-APC interaction must be stabilized by integrins. LFA-1 will bind to ICAM-1 on APCs
What does exposure to chemokines do to LFA-1?
It converts LFA-1 to a high affinity state that clusters within minutes
So, T cells bind aPC strongly and thus activation of the TCR is strengthen
What does further signaling do to the affinity of LFA-1 for ICAM-1?
It strengthens the affinity of LFA-1 for ICAM-1 which will increases the strength of the T cell - APC interactions and further stabilizes T cell signaling
What happens at the same time as peptide presentation?
Microbial PAMPs stimulate expression of costimulators on APCs so that T cells that respond to MHC-microbial antigen complexes also receive a second signal
What is the three-signal hypothesis?
Signal 1 = antigen-specific TCR engagement of MHC and peptide
Signal 2 = contact with costimulatory ligands
Signal 3 = cytokines directing T-cell differentiation into distinct effector cell types
Define differentiation
The process by which a cell becomes distinct of specialized, acquiring functionality lacking in naive cells
What does TCR signaling result in?
Changes in gene expression will lead to the differentiation of naive T cells into CD4 and CD8 T cells
What does differentiation coincide with?
Clonal expansion and leads to the generation of large numbers of differentiated effector cells
What do type 1 CD4 T cells (TH1) respond to?
Intracellular pathogens inducing cell-mediated immunity
What do type 2 CD4 T cells (TH2) respond to?
Pathogens inducing humoral immunity particularity extracellular parasites
What do CD4 effector cells produce?
Surface molecules and cytokines that mainly activate macrophages and B cells
What do active CD4 T cells express and why?
They express the surface molecule CD40L which bind to CD40 on macrophages, B cells, and dendritic cells
This binding activates macrophages and B cells
What do dendritic cells increase the expression of?
Costimulators which further activates CD4 T cells
What is the most important cytokine produced by type 1 helper cells and what does it do?
IFN-gamma
It is a potent activator of macrophages - enhances microbial killing
Stimulates B cells to produce antibody isotypes that promote the phagocytosis of microbes
What does CD8 differentiation (TH1) support?
The activation and differentiation of CD8 cytotoxic T cells
Initially there is a lot of clonal expansion but as the infection clears that population dies off or differentiates into a smaller population of CD8 memory cells
How do CTLs kill target cells?
Up close to avoid damage to non-target cells
Perforin in the synapse between a CTL and a target cell perforates the target cell membrane allowing apoptosis inducers inside
How are T cells activated?
Activated T cells produce cytokines that drive clonal expansion
Some of the activated T cells differentiate into effector cells to destroy microbes, other become memory cells
What are memory T cells?
They are functionally inactive, long-lived, and respond rapidly to the same microbe
What are cytokines produced by and how do they act?
Produced by macrophages and T cells (CD4 in particular)
Production is transient to regulate immune responses and they act in paracrine or autocrine manners to stimulate multiple arms of the immune response
Are there more CD8 cells or CD4 cells?
CD8
Where do memory T cells reside?
In lymphoid tissues
Mucosal barriers
Circulation
Why are memory T cells functionally inactive?
They do not continue to produce cytokines or kill infected cells but may do so rapidly upon reinfection
Why might a T cell become anergic?
An MHC molecule presented a peptide but the T cell does not receive a second signal
What do anergic T cells provide protection to?
Auto-reactive lymphocytes in the periphery
What is the solution to this barrier?
T cells must encounter antigen
APCs concentrate antigens in the lymphoid organs
What is the solution to this barrier?
T cells must determine the appropriate response (CD4 or CD8)
Class I and Class II MHC molecules direct the specificity of the response
What is the solution to this barrier?
T cells must encounter antigen long enough for T cell signaling to occur
Adhesion molecules tighten interactions between T cells and APCs
What is the solution to this barrier?
The T cell response must be directed against microbial antigens and not harmless proteins
2nd signal ensures responses are elicited against microbial antigens
What is the solution to this barrier?
A small number of T cells have to mediate the initial response
Amplification mechanisms boost the T cell response
clonal expanision, cytokine production
