Cell Mediated Immunity

Question 1

Cell Mediated Immunity: Ag Specific

Answer 1

Cell-mediated effector mechanisms (transferable with cells) protective against intracellular infection and tumor cells

All immune responses are polyclonal – peptide is cleaved into many and activate multiple T cells

Antigen-specific, acquired immunity:
Cytotoxicity by cytotoxic T cells (TC)
Helper T cell (TH)-dependent “macrophage activation” (enhanced intracellular killing by macrophages stimulated by cytokines from antigen-specific T helper cells)

Question 2

T cytotoxic vs. T helper Killing

Answer 2

Cytotoxic cells protect against intracellular pathogens (inside infected cells) and recognize the microbes and kill the infected cells and eliminate reservoirs of infection

Phagocytosed microbes in macrophages can resist killing, so then T helper cells release cytokines, INF gamma, and activate macrophage and able to kill the microbes

Question 3

Two Signal Requirement for T cell Activation by Antigen

Answer 3

Two signal requirement for T cell activation to prevent autoimmunity and reaction to self peptides

1. Antigen recognition through the receptor
2. Signals from macrophages only induced in presence of pathogens along with co-stimulatory signals if interacting with a microbe

Question 4

T Lymphocyte Activation

Answer 4

Constantly sample external environment
Any nucleated cell will present cytosolic proteins
IL-2: T cell growth factor and activate genes to make the IL-2 molecule and IL-2 receptor = autocrine response

Naïve CD4 cell is releasing IL-2 and responding to it to get lots of IL-2 generation and drive CD4 T cells to proliferate into effector and memory CD4 T cells

Receptor expression needs to be regulated and only expressed with pathogen because if T cell expressed this all the time, you would always respond to IL-2 and too much proliferation

Question 5

CD4 vs. CD8 Response to Ag

Answer 5

CD4 are regulatory and activate macrophages, B cells, inflammatory disorders (some), and when they see Ag they release growth and differentiation factors for these activations

CD8 are cytotoxic and must acquire it when Ag is presented by APC and then goes to periphery and kill infected cells and activate macrophages
Everything is regulated and activated by antigen and have long half life and provide protection on reexposure and are rapidly activated and differentiated and rapidly expand if presented with same Ag
Ag specific proliferation – T cells response only to Ag stimulus

Question 6

T cell Maturation

Answer 6

T cells mature in the Thymus
Each clone expresses a unique antigen specific receptor (T cell receptor = TcR) generated by random DNA recombination of multiple gene segments encoding TcR protein chains.
~1016 possible different receptor combinations
Immature T cells with autoreactive receptors are deleted by apoptosis (clonal deletion)

Question 7

Ag Activated T cell Functions

Answer 7

T cells do not secrete a soluble form of the TcR

CD4+ T helper cells (TH) secrete cytokines (growth and differentiation factors for immune cells)

CD8+ Cytotoxic T cells (TC) acquire cytotoxic function

Question 8

Lab Markers for T cells

Answer 8

Surface abTcR/CD3 plus CD4 or CD8
CD4+ T = T helper cells
CD8+ T = T cytotoxic cells

CD3 is important for cascade signaling; marker for all T cells and signals cells to become activated

CTLA -4 – turn off T cell

Question 9

T cell Recognition of Ag

Answer 9

TcR bind foreign “peptides” that are “presented” as a “peptide-MHC” complex on the cell membrane of self cells
MHC = major histocompatibility complex proteins = self tissue markers
MHC I molecules are on all nucleated cells
MHC II molecules are only on APC (antigen-presenting cells such as macrophages, B cells, and dendritic cells)

Question 10

TCRs

Answer 10

TCRs are a univalent, clonotypic, ab (90-95% of T cells) or gd heterodimeric membrane proteins, not secreted

Transmembrane protein with alpha and beta chains = heterodimer
Exposed loops form the binding site and recognize MHC complex
Since they bind different peptides, the alpha and beta fold to create the unique site
2 polypeptide chain structure transmembrane protein and has one binding site per receptor

Question 11

MHC-Peptide Complexes

Answer 11

T cell receptors only recognize MHC-peptide complexes
Multiple MHC genes, but single MHC molecule can bind multiple different peptide but share common structural motif
T cells recognize chemicals on both self MHC and peptide when TOGETHER

Question 12

Rationale for T cell Recognition of “Processed” Peptides

Answer 12

Immunity to extracellular vs. intracellular foreign molecules requires different mechanisms
Antibodies protect against extracellular antigens
TC protect against intracytosolically-infected cells or tumor cells with altered cytosolic proteins

The extracellular vs. intracytosolic origin of foreign proteins directs the activation of TH vs. TC cells.
Extracellularly-derived proteins are “processed” in a manner to complex with MHCII to activate TH cells.
Intracytosolically-derived proteins are “processed” in a manner to complex with MHCI to activate TC cells

Question 13

Mechanism for Presenting Peptides to CD4 vs. CD8

Answer 13

CD4: T cells can only react to class II MHC which are extracellular derived peptides (endocytosis of peptide is necessary into APC); Within ER, peptide binding site MHC II is blocked from picking up peptides from ER until fusion of phagosome and release of invariant chain exposing peptide binding site on MHC II for self and non-self peptides and then go to APC surface and display the peptide to cause T lymphocyte activation (CD4)

CD8: if problem in cell (cytosol)/intracellular – packed into short peptides via proteasome and transported to ER and complexes are formed and are picked up by class I MHC to be expressed

APC: dendritic cells, macrophages, and B cells, all are unique and express genes for MHC II formed in ER and can traffic through membrane bound vesicle and go to the cell surface

Question 14

APCs

Answer 14

Only Dendritic cells, macrophages, and B lymphocytes are good APC because they express MHC II and co-stimulatory molecules required to activate naïve TH cells

Dendritic cells – constantly trapping and processing proteins and react with MHC II; drive activation of naïve T helper cells

Macrophages – not as important as dendritic in primary reactions, but specialize in processing and presenting Ag from ingested pathogens

B cells: specialize in Ag specific processing and presentation of soluble Ag; are not phagocytic

Question 15

Foreign Intracellular Ag Examples that Elicit CD8

Answer 15

Virus infection and host synthesis of viral proteins
Replication of intracellular bacteria in host cell cytoplasm
Protein antigen of ingested microbe transported to cytoplasm
Expression of mutated self proteins in cancerous cells

Question 16

Co-Stimulatory Signals for T cell Activation with APC

Answer 16

Most of the time they are presenting self peptides, and if auto T cells will go through a process called anergy and undergo apoptosis and death
If CD28 interacts on T cells interacts with B7 (co-stimulatory molecule) on APC – causes proliferation and differentiation of effector and memory T cells via gene transcription for production of IL-2 and IL-2 (because autocrine signaling)

Costimulatory signal goes from APC to T cell for upregulation of CD40 ligand on T cell membrane, which interacts with CD40 on APC to enhance APC functions including B7 expression, macrophage activation, B cell class switching and B memory.

Question 17

How do infected non-immune cells that do not express costimulatory signals activate Tc?

Answer 17

Cross-presentation by DC
DC can ingest other infected cell types and “cross-present” ingested antigens on both MHC 1 and MHC II to simultaneously activate TH and TC
Th-DC interaction via CD40L-CD40 probably upregulates DC expression of membrane 4-1BBL necessary for Tc activation on the same DC.
Mature DC express serine protease inhibitor (SPI)-6 that protects them from Tc cytotoxicity.

Question 18

DC Presentation from Periphery to Activate T cells

Answer 18

“Immature” phagocytic DC in tissues are activated by pathogens via TLR (interaction with PAMPs) or by inflammatory cytokines to:

Express CCR7 and Migrate to lymph node
“Process” ingested proteins into peptides
“Present” MHC-peptide complexes, adhesion molecules, and co-stimulatory molecules on DC membrane necessary for T cell activation
“Mature” DC efficiently “present” antigen and co-stimulatory signals to naïve TH cells via MHCII and to naive TC via MHC I.

Question 19

Deficiency in CMI Functions

Answer 19

Deficiency in cell-mediated immune (CMI) functions predisposes individuals to infections by intracellular microbes:
Facultative intracellular (Intravesicular) bacteria
Viruses
Intracellular fungi or parasites

Deficiency in CMI is also believed to associated with increased cancer risk
Chronic CMI responses are associated with tissue injury to self tissues as in tuberculosis and asthma. (Target of immunotherapy)
Delayed type skin tests (DTH, as for TB skin test) are clinical measures of CMI responses and are evidence of microbial exposure

Question 20

Superantigens

Answer 20

Microbial Superantigens nonspecifically bind TcRs and activate nonspecific T cell proliferation

Question 21

MHCs

Answer 21

Multiple inherited forms (alleles) of each MHC gene (=HLA gene)

3 MHC I genes (HLA-A,-B,-C) and 3 MHC II genes (HLA-DR,-DP,-DQ) inherited from each parent, co-dominantly expressed on cells.

Degenerate specificity = each MHC protein can bind many structurally different peptides that share certain “chemical motifs”.
MHC I expressed on all nucleated cells (including APC!)
MHC II expressed only on APC