(I) Lecture 7: T cell Immunity Part II Flashcards
Where do lymphocytes develop?
B cells develop in the bone marrow
T cells start in the bone marrow then finish developing in the thymus
Where are lymphocytes activated and differentiated?
In the secondary lymphoid tissue
Adaptive immunity specificity
B and T cells express many exact copies of a receptor w/ a unique antigen binding site
T cell receptors
Each T cell has a TCR with a variable region specific for one unique peptide even if there are multiple TCRs on a T cell
Types of effector T cells
Helper cells (CD4+) = exogenous (MHC Class II)
Cytotoxic T cells (CD8+) = endogenous (Class I)
Cytosolic pathogens
- degraded in cytosol
- peptides bind to MHC Class I
- presented to CD8 (cytotoxic) T cells = cell death
Intravesicular pathogens
- degraded in endocytic vesicles (low pH)
- peptides bind to MHC Class II
- presented to CD4 (helper) T cells = activation of macrophages to kill intravesicular bacteria and parasites
T cell differentiation
- antigen recognition
- activation
- clonal expansion
- differentiation
- effector functions
CD4 function
activation of macrophages, B cells and other cells
Recognize complex of bacterial peptide w/ MHC Class II and activates macrophage
- help macrophage phagocytose better (induce fusion of phagolysosome or improve outcome of phagocytosis)
CD8 function
killing infected “target cells” AND macrophage activation
Recognizes complex of viral peptide w/ MHC class I and kills infected cell
T cell activation
Thymus –> SLT –> site of infection
naive T cells enter SLT looking for their respective antigens/pathogens (activated by DC)
effector T cells are activated then leave SLT and enter infected tissue (innate signaling) to either kill (CTL) or “help” (Th) control the infection – proliferate and eliminate infection
SLT
Secondary Lymphoid Tissue
SLT (lymph nodes, spleen, MALT) are specialized to facilitate interaction of circulating T and B lymphocytes with their antigen
Lymph node and T cell activation
Antigen comes in lymph (either free antigen or bound to DC)
In T cell zones, naive T cells can recognize antigen on the surface of DC
Effector T cells leave lymph node to travel to infected tissue
Antigen Presenting Cells
- INITIATE adaptive response
- presents pathogens: expresses antigens of pathogens on their surface on MHC I or II
- migrate to SLT and to T cell zones
- ONLY DCs can activate naive T cells
How are naive T cells activated?
Through MATURE dendritic cells (DCs)
Ways that an APC can engulf antigens
- Phagocytosis through a phagolysosome
- Pinocytosis: macrophages and DCs engulf fluid by protruding actin filaments (endosome)
- Endocytosis: B cells can use endosomes to engulf pathogens
Result in loading of antigenic peptides onto MHC Class II
Dendritic cells roles (maturation)
Immature DC: phagocyte (innate immunity)
Mature DC: antigen presentation (adaptive immunity)
Dendritic cell maturation steps
DCs mature after they travel in lymphatic tissue
- immature DCs live in peripheral tissues
- DCs migrate via lymphatic vessels to lymph nodes
- Mature DCs activate naive T cells in lymphoid organs like lymph nodes
DCs and receptor-mediated phagocytosis
- Pathogen presented: extracellular bacteria, fungi
- Presented to: MHC Class II
- Activates CD4 T cells
DCs and macropinocytosis
- Pathogens presented: extracellular bacteria, soluble antigens, virus particles
- Presented to: MHC Class II
- Activates CD4 cells
DCs and viral infections
- Pathogens presented: viruses (ENDOGENOUS)
- Presented to: MHC Class I
- Activates CD8 cells
DCs in SLT
- antigen presentation
- trigger clonal expansion and differentiation
- CD4+ gives rise to T helper cells
- CD8+ gives rise to cytotoxic T cells
Constant activation of T cells
Can lead to severe outcomes like superantigens
Signals of T cell activation
- TCR binding to antigen/MHC
- Costimulatory receptors (expressed only by APCs)
- Cytokines (secreted by APCs)
ALL three must be present for full activation and clonal expansion
T cell anergy
Lack of costimulatory receptor (non-APC cell) fails to activate T cell
- good b/c you don’t want T cells attacking good cells
Anergic T cell continues through circulation w/o activity
Good CHECKPOINT: stops autoreactive T cells
How do CTL cells kill infected cells?
They kill cells infected w/ intracellular pathogens like viruses via induced cell-mediated APOPTOSIS
CTLs have granules loaded w/ toxic stuff that migrate to site of infection and releases substances (like w/ NKCs)
Perforin
In CTL granules
- form pores in membrane of target cells
- helps in delivering contents of granules into cytoplasm of target cell
Granzymes
In CTL granules
- degrades DNA of target cell = triggers APOPTOSIS
CTL steps
- motile mouse CTL approaches target cell
- initial contact
- start of exocytosis (granules fuse w/ CTL cell membrane and perforin is released)
- granules congregate to CTL/TC (target cell) contact
- more granules migrate
- granzyme starts a cascade of rxns that fragment target cell DNA = APOPTOSIS
- viral RNA is also degraded
Viral infection course of response
- Virus infected cells release IFNs
- IFN stimulates NK cells which kill virus-infected cells and help control infection WHILE CTLs generate
- CTL continues to kill virus-infected cells = infection is controlled
T helper cell response
T helper cells regulate immunity to intravesicular pathogens
Secrete IFN-gamma which enhances phagocytosis
T helper cells also form a granuloma if intracellular pathogen can’t be completely cleared
IFNs
IFN alpha and beta activate NKCs
IFN gamma enhances phagocytosis (from TH1)
Granuloma
A BARRICADE around infected macrophages if intracellular pathogens can’t be completely cleared
SCID
Severe Combined ImmunoDeficiency
ABSENCE of functional T cells
- severe medical emergency = fatal w/o treatment
- no T cells = no activation of B cells (combined)
- infants w/ SCID die quickly from infections w/ opportunistic pathogens
- newborn screening = early treatment
- preventative treatment = prophylactic antibiotics + IVIG
- Cure: hematopoietic cell (bone marrow) transplant
AIDS
Acquired Immune Deficiency Syndrome
- associated w/ Human Immunodeficiency Virus (HIV)
- contact w/ virus does not necessarily mean infection
- infection rate depends on route of contact (blood contact is highest)
- no cure or vaccine yet
Treatment: antiretroviral therapy
CD4 cells and HIV
CD4 is a receptor for HIV and binds to constantly activate T cells to point of T cell exhaustion = DECREASE in number of T cells
Frequent opportunistic pathogens = death
Seroconversion
anti-HIV antibodies
An effector T helper cell response is likely to result in
- formation of a granuloma (for TB)
- production of IFN-gamma (activates macrophages)
Apoptosis
- occurs at end of a cell’s lifespan (natural)
- can be triggered by granzyme
- kills infected cells
What can contribute to elimination of intracellular virus?
- MHC I molecules (endogenous peptides)
- CTL
- NK cells
- Type I IFN (activates NKCs)
