T Cell Mediated Immunity

Question 1

Effector T cells have 3 primary functions in combatting infection:

Answer 1

1. Secrete cytokines that will stop microbial replication and/or activate phagocytes to become better killers of pathogens they ingest (CD4 T cells).
2. Provide cytokines and cell-cell signals to B cells to help the antibody and CD8 T cell responses (CD4 T cells).
3. Directly kill the microbeinfected cells (mainly CD8 T cells, and some CD4 T cells)

Question 2

There are 5 phases to T cell activation: Phase 1

Answer 2

1. Naïve T cells can only be activated by dendritic cells (DC) presenting their cognate antigenic peptide in the context of MHC (pMHC). Additional activating signals must be presented by the same DC presenting the pMHC.

Question 3

There are 5 phases to T cell activation: Phase 2

Answer 3

2. Upon activation by the DC, activated T cells produce cytokines, such as IL-2, which provide an autocrine growth signal to themselves.

•Remember – the mature DC is also simultaneously producing its own cytokines (the type of cytokine produced is dictated by which PRR (pattern recognition receptor) is triggered) to “instruct” the activated T cell as to what type of response is required to optimally fight this particular infection. Once instructed, T cell will make cytokines best suited to eliminate this particular type of infection.

Question 4

There are 5 phases to T cell activation: Phase 3

Answer 4

3. Activated T cells undergo clonal expansion, producing replicates of themselves – each cell can divide up to 20 times (as can each daughter cell produced), with doubling rates as fast as every 2-6 hours.

•Steps 1-3 occur in 2° lymphoid organs, which explains lymphadenopathy during the early stages of infection.

Question 5

There are 5 phases to T cell activation: Phase 4

Answer 5

•Many of the clonal progeny differentiate into effector T cells, via programmed changes in gene expression to allow them to produce molecules to combat the infection and/or aid other immune cells. These cells migrate out into peripheral tissues, fight the infection and, upon elimination of the microbe, eventually most die by apoptosis.

Question 6

There are 5 phases to T cell activation: Phase 5

Answer 6

5. A small subset of the clonal progeny is maintained as long-lived, stable memory T cells, which respond rapidly upon reinfection with the same pathogen. Memory subsets are maintained both in 2° lymphoid organs (central memory), as well as in the tissue sites of the initial infection (tissue and effector memory).

Question 7

Multiple signals are required for the activation of naïve T cells:

Question 8

Answer 8

• The TCR cannot be expressed on the cell surface alone, nor can it transmit signals to the cell that antigen has been recognized. These functions (stability and signal transduction) are provided by the CD3 complex.
• The CD3 complex is composed of g, δ, ε and ζ protein subunits. These chains play a role in intracellular trafficking/assembly, T-cell development and signal transduction to promote T cell activation.

Question 9

Answer 9

• The first signal in T cell activation is provided by T cell receptor (TCR) recognition of peptide-MHC, as well as coreceptor (CD4 or CD8) binding to the same MHC.
• The TCR interacts with both the antigenic peptide and the MHC molecule.
• Within the variable domain of the TCR, complementary determining regions 1 and 2 (CDR1 and CDR2) interact mostly with MHC.
• The most variable CDR3 regions of both TCRa and b chains (which span the VDJ recombination sites) dominantly interact with peptide antigen (Ag) in MHC groove.

Question 10

Answer 10

• The costimulatory signal passed through CD28 works in cooperation with the TCRmediated signal to activate naïve T cells. TCR stimulation in the absence of CD28- mediated costimulation often renders that T cell “tolerant” and unable to be activated in the future.
• The expression of B7-1 and B7-2 on APC is controlled by microbial sensing through the PRRs (for details see Chapter 2) – so that immature or resting APC express very little of these costimulatory molecules. Upon infection, pathogen components are recognized by PRRs, leading to APC maturation, and the upregulation of costimulatory molecules.

Question 11

Answer 11

Question 12

Answer 12

Question 13

Answer 13

• Adhesion molecules are critical in stabilizing the T cell-APC interactions to allow sufficient time for the TCR to sample the pMHC complexes on a given cell, in search of their antigen.
• Further, once a T cell recognizes its antigen, the T cell-APC interaction must remain stable long enough for the TCR to transmit the signal into the cell to begin the activation process. Two key adhesion molecules expressed on T cells are members of the integrin family, and interact with their ligands on the APC surface: • Naïve T cells express leukocyte function-associated antigen 1 (LFA-1) which binds to intercellular adhesion molecule 1 (ICAM-1) on APC.
• Activated T cells upregulate expression of both LFA-1 and other adhesion molecules, including VLA-4 (very late activation antigen 4). This integrin interacts with vascular cell adhesion molecule-1 (VCAM-1), which is expressed on the endothelium of blood vessels near the sites of inflammation. Thus, during the process of activation, T cells turn on adhesion molecules that will facilitate migrate to sites of infection.

Question 14

Activated T cells upregulate expression of both LFA-1 and other adhesion molecules, including []. This integrin interacts with vascular cell adhesion molecule-[], which is expressed on the endothelium of blood vessels near the sites of inflammation. Thus, during the process of activation, T cells turn on adhesion molecules that will facilitate migrate to sites of infection.

Answer 14

Activated T cells upregulate expression of both LFA-1 and other adhesion molecules, including VLA-4 (very late activation antigen 4). This integrin interacts with vascular cell adhesion molecule-1 (VCAM-1), which is expressed on the endothelium of blood vessels near the sites of inflammation. Thus, during the process of activation, T cells turn on adhesion molecules that will facilitate migrate to sites of infection.

Question 15

Following TCR and CD28 stimulation, [] is upregulated on activated T cells. This molecule interacts with [] on APC in a positive feedback loop, resulting in further upregulation of B7-1 and B7-2 on the APC, and additional cytokine secretion capacity.

Answer 15

Following TCR and CD28 stimulation, CD40L is upregulated on activated T cells. This molecule interacts with CD40 on APC in a positive feedback loop, resulting in further upregulation of B7-1 and B7-2 on the APC, and additional cytokine secretion capacity.

• Thus, upon successfully activating a T cell, the APC is rewarded with a signal back that makes that APC even more effective at activating additional T cells.
• In addition, CD40L expression plays a critical role in T cells providing help to B cell responses (in particular for isotype switching).

Question 16

[] is responsible for naïve cell recruitment and retention in the lymph nodes. Expression is lost following T cell activation. Various ligands are expressed on endothelial cells, including [] on the high endothelial venules in lymph nodes, allowing naïve cells to enter.

Answer 16

CD62L (L-selectin) is responsible for naïve cell recruitment and retention in the lymph nodes. Expression is lost following T cell activation. Various ligands are expressed on endothelial cells, including GlyCAM-1 on the high endothelial venules in lymph nodes, allowing naïve cells to enter.

Question 17

Special Cases of Signal 1: Superantigens

Answer 17

• SUPERANTIGENS (SAG) are viral or bacterial derived proteins that stimulate very large numbers of T cells.
• Typically, superantigens directly bind to both the TCR and MHC class II chains without MHC processing.
• Thus, they form a molecular bridge that “ignores” the specificity of the TCR for pMHC and glues them together, binding many T cells to antigen-presenting cells regardless of their TCR specificity.
• Massive cytokine release occurs from this large population of activated T cells upon superantigen binding. This results in systemic toxicity to the host.
• Symptoms include diarrhea and weakness, as a result of the massive “cytokine storm”.

Question 18

Special Cases of Signal 1: Alloreactivity

Answer 18

• ALLOREACTIVITY Responses to any given peptide of a microbe involve a few thousand cells, making up 0.0001% or less of total T-cells in the body.
• By contrast, nonself (allogeneic) MHC is recognized by 1-10% of T cells.
• Allogeneic MHC differs from syngeneic MHC (to which self T cells are tolerant) at the regions where CDR1, CDR2 or CDR3 dock. This stimulates many T cells (normally specific for self MHC and foreign peptide) – which is called direct alloreactivity.
• The other “allo” response is self-MHC presenting allo MHC peptide (indirect).
• An ”allo“ response is very strong because it activates a huge number of T cells and is the cause of organ and bone marrow transplant pathology.

Question 19

No Signal 1 + Signal 2 or 3 =

Answer 19

nothing!

Question 20

Signal 1 + No Signal 2 or 3 =

Answer 20

tolerance!

Question 21

Signal 1 + Signal 2 or 3 =

Answer 21

activation/immunity!

Question 22

Activation of Naive CD 8 cells:

Answer 22

1. The professional APC (DC) is itself directly infected by the microbe, and it processes and presents class I peptides.
2. CROSS PRESENTATION! DC ingest material from other infected cells and cross present it on its own MHCI molecules. Because of the rarity of direct DC infection by microbes, cross-presentation is likely the dominant and most important pathway for naïve CD8 T cell activation.

Question 23

CD4 help for CD8 T cell activation

Answer 23

• There is often a coordinated interaction between CD4, CD8 and APC to allow for successful immune responses.
• Such coordination occurs because both CD4 and CD8 T cells can recognize antigens derived from the same pathogen, and being presented by the same APC (albeit presented by different MHC molecules). This process is often described as CD4 help to CD8 responses (Fig. 7-7), as antigen recognition by the TH1 CD4 helper cell helps support CD8 T cell activation.

Question 24

A virus will stimulate [] or [] on a DC, triggering production of [] and []. What will this tell the naive T cell?

Answer 24

A virus will stimulate TLR3 or TLR7-9 on a DC, triggering production of IFN-I and IL-12.

• This will instruct the uncommitted naïve T cell (T0) to become a TH1 T cell that will make IFNg, TNFa and lytic molecules to kill infected cells.
• This will be the case for all viruses, intracellular bacteria and intracellular fungi (although each will be sensed by different classes of pattern recognition receptors, PRR).
• These TH1 cells/cytokines have roles in chronic inflammation and autoimmunity.

Question 25

An extracellular helminth will stimulate [] and other sensors on a DC, triggering production of []. What will this tell the naive T cell?

Answer 25

An extracellular helminth will stimulate TLR2 and other sensors on a DC, triggering production of IL-4.

•This will instruct the uncommitted naïve T cell (T0) to become a TH2 T cell that will make IL-4, IL-5, IL-9, IL-13 (IL-9 and 13 may be made by a new subset, now called Th9) and other TH2 cytokines that help support efficient B cell activation/antibody production.

•In addition, some of these TH2 cytokines have roles in allergy

Question 26

An extracellular gut bacterium will stimulate [] on a DC, triggering production of []. What will this tell the naive T cell?

Answer 26

An extracellular gut bacterium will stimulate TLR1,2, 4&5 on a DC, triggering production of IL-6 & TGFb (and sometimes IL-23).

•This will instruct the uncommitted naïve T cell (T0) to become a TH17 T cell producing IL-17 and IL-22 (to support mucosal integrity).

•In addition, these TH17 cells/cytokines play roles in autoimmunity.

Question 27

An unknown tolerogenic signal from a microorganism or self-tissue damage will stimulate yet unidentified sensors on DC, triggering production of []. What will this tell the naive T cell?

Answer 27

An unknown tolerogenic signal from a microorganism or self-tissue damage will stimulate yet unidentified sensors on the DC, triggering production of TGFb.

•This will instruct the uncommitted naïve T cell (T0) to become a TREG cell that will make CTLA-4 and IL-10, inhibiting the activation of autoreactive T cells. Secretion of IL-6 may cause inhibition of TREG cell differentiation.

Question 28

Effector memory T cells

Answer 28

Effector memory T cells are able to rapidly produce cytokines upon re-exposure to their antigen. These cells can be found within tissues (often the site of original infection) –and are thus classified as tissue-resident memory cells. Some of them can also circulate throughout the body.

Question 29

Central memory T cells

Answer 29

Central memory T cells are primarily found in secondary lymphoid organs (spleen, lymph nodes). Upon re-exposure to antigen they primarily undergo rapid proliferation to produce another clonal population of effector cells to migrate back to the site of infection for pathogen clearance.