9_t_cell_mediated_immunity.md

T Cell Mediated Immunity

Primary lymphoid tissues - bone marrow + thymus. Secondary lymphoid tissues - lymph nodes, spleen, tonsils, mucous membranes (bowels/intenstine)

Naive T cells circulate between blood and lymphatic tissue.

CD4 Effector Subsets include TH_1, TH_2, TH_17, TH_FH + T_reg.

Priming (to distinguish from productive response)

• recognition of MHC:peptide
• binding to costims
• stimulation by cytokines to lead down particular effector path

Descriptions of Lymphoid Tissues

Spleen captures antigens from the blood stream.

• Central arteriole brings blood to the spleen.
• Branching parts of arteriole end in the marginal sinus.
• Marginal sinus separates arteriole from white pulp
• White pulp is the lymphoid compartment:
• B cell zone
• T cell zone wraps the arteriole on the outside of the marginal sinus (Periarteriol lymphoid sheath)

Lymph Nodes

• connected to both blood and lymphatic system
• enter from blood in HEVs (High Endothelial Venules)

Mucosa Associated Lymphoid Tissue (MALT)

B cells and T cells are seperated into distinct zones in all three lymphoid tissue types. Line epithelial tissues.

The Development of Secondary Lymphoid Tissues is controlled by TNF proteins + Lymphoid Tissue Inducer Cells

Lymphoid Tissue inducer Cells migrate from the bone marrow (where they are derived from HSPCs).

They express TNF family proteins - LT_\alpha + LT_\beta. These chemokines cause stromal cells at the precurso sites of 2nd lymphoid tissue, eg. Peyer's patches, to expresss TNFRs.

This causes stromal cells to express CXCL13, which recruits more lymphoid cells from the marrow.

Chemokines direct T and B cells into their respective compartments

CCL21, CCL19 are the chemokines that attract T cells. CCL7, receptor expressed by T cells (and dendritic cells), responds to ^

When they are recruited, the T-cells themselves start to express these chemokines

CXCL13 (B Cell chemokine)

Naive T Cells Migrate thorugh Secondary Lymphoid Tissue

Clonally expand + differentiate into effector and memory cells with antigen specificity. Lymph ti

Entry of Lymphocytes into Lymphoid tissues requires concerted interaction of chemokines + integrins

1. Rolling
2. Activation
3. Adhesion
4. Diapedesis (enter)

Selectin is a protein largely conserved with a different carbohydrate recognition motif.

• P-sellectin (macrophages)
• E-selectin (vascular endothelium)
• L-selectin (naive T cells)

Binds to vascular adressins (loose term for class of "adressing" molecules) found on the HEV - CD34 + GlyCAM-1.

Activation of integrins by chemokines is responsible for the entry of lymphocytes into lymphoid tissue

Properties of integrins:

• Composed of alpha and beta chain.
• Subfamilies are defined beta chains.
• Bind tightly to ligands after receiving signals that cause changes in their conformation

T-cell integrin or LFA-1 (Leukocyte Family Antigen 1). Binds to ICAM-[1-3]. Is activated by proximity from selecting rolling

CCL21 bound to the HEV (the same that direct them to the correct compartment) causes integrins (like LFA-1 to change conformation) when bound to . Once bound to ICAM, the lymphocyte migrates into the lymphoid tissue.

T-cell responses are initiated in the secondary lymphoid organs by activated dendritic cells

Dendritic cells can be activated by:

• TLRs or other pathogen recognition receptors
• Tissue damage
• Cytokines from infllamation

Activated DCs migrate to the lymph and express costims + antigens needed for TCR binding.

Macrophages + B cells also present antigens. Distribution in tissue differs. Type of interaction with T cell also differs:

• DCs initiate first response for clonal expansion + differentiation
• B cells + macophages mostly present soluble antigens + intracellular pathogen antigens. Recruit primed CD4 T cells.

Dendritic cells process antigens from a wide array of pathogens

Dendritic cells originate from myeloid progenitors in bone marrow. There are two types:

• conventional

• plasmacytoid

• Are abundant in barrier tissue sites

• complement receptors

• Fc receptors

• C-type lectins

• general uptake of fluid with macropinocytosis

• Phagocytosis (II)

• Macropinocytosis (II)

• Virus (I)

• Cross presentation from phago/macropino (I)

• Sharing (eg. Herpes Simplex) (II)

Microbe induced TLR signaling induces migration to lymphoid tissues + kicks off antigen processing

Activation is also called licensing

Different receptors provide maturation signals:

• TLRs
• dual effector function of phagocytosis receptors
• lectin

Then produces CLL7, so it will migrate to CCL21/CCL19 producing cells in secondary lymphoid tissues

Once in there

• High levels of MHC1/MHC2
• Co-stim CD80 / CD86
• Cease ability to perform phagocytosis or macropinocytosis

The activation of co-stims is believed to distinguish self-protein presentation from pathogen-protein presentation. The former does not activate costims. Molecules that do are called adjuvant.

Plasmacytoid DCs help T-cells but aren't relaly invo

Help conventional dendritic cells produce IL-12, which is needed by CD4 T-cells for production of IF-\gamma.

B cells and macrophages seem to use antigen presentation to enhance their own responses

• surface immunoglobulin with antigen <> primed CD4 T-cell -> antibody secreting B cell

Macrophage production of MHC I/II + B7 seems to be far more for maintainence + functioniong of effector / memory T cells than any priming. Induced by recognition of MAMP

Main function in lymph tissues is actually ingestion of stray pathogens / apoptotic lymphocytes to keep them from entering the blood.

Priming of naive T cells by pathogen activated dendritic cells

Cell adhesion molecules facilitate initial interaction of T cells with dendritic cells

LFA / CD2 <> ICAM1/ICAM2 When T-cell recognizes an MHC:peptide complex, LFA changes its conformation to bind more stably to ICAM.

Multiple signals are involved with the activation + proliferation of naive T-cells

• Activation (MHC:peptide)
• Survival + Expansion (Co-stims)
• Differentiation (Cytokines)

B7 family ligase (acting on CD28) is the common costim molecule. Binding with antigen:MHC is not enough to "prime".

Antigen presenting cells deliver multiple signals for the clonal expansion and differentiation of naive T-cells

Useful to consider three types of signals necessary for T-cell differentiation.

1. MHC:peptide <> TCR
2. Costim
3. Effector cytokines (more later)

CD28 co-stimulation of activated T-cells induce IL-2 and IL-2R

Costims kick T-cell into G1 and induce expression of the missing \gamma chain from IL-2R and the expression of the cytokine IL-2 itself.

T_reg cells express a more sensitive form of IL-2, which is one mechanism for suppressin of T-cell activity

Recall, IL-2 is induced in 3 ways from costim:

1. AP-1, NFAT from PI-3 Kinase activation downstream of ITAM
2. Increase longevity of cytoplasm transcript
3. PI-3 Kinase leads to Akt which prolongs the life of the cell

Additional co-stim pathways are involved in T-cell activation

After activation, additional costim receptors are expressed that are important to know:

• B7 costims <> CD28 related receptors - ICOS, CTLA-4
• TNF receptor family. Generally all activate NFkB (CD40, CD27, 4-1BB)

Proliferating naive T cells differentiate into effector T cells that do not require costims to act

4-5 days of cell division transform into cells with specific responses upon recognition of antigen.

Best seen by CD8, cytotoxic, cells that should not require CD8 present on surface of eg. cell infected with a virus

Change repertoir of expressed surface molecules

• Reduce L-selectin -> no longer recirculate through lymph nodes
• Express P/E-selectin on surface of vascular endothelium -> migrate from bloodstream to sites of infection

CD8 T cells are often activated by CD4 T cells

CD8 effects are strong and require more costim than CD4 for priming. CD4 T cells often bind to APC and induce expression of B7 + 41BB-L to facilitate CD8 development. They need "extra help".

CD4 T cells differentiate into different types of effector cells

Simply memorizing the names, effector molecules, recruited immune cells and function is highest leverage here.

T_H_1. IFN-\gamma. Recruit macrophages. Kill internal bacteria like mycobacterium (Tuberculosis) T_H_2. IL-4/IL-6 (bone marrow) + IL-13 (goblet cell). Recruit basophils, eosionophils, mast cells. Kill Helminth parasites (tapeworms) T_H_17. IL-17 (stroma). IL-22 (epithelial). Recruit neutrophils. Kill extracellular bacteria like pneumoniae. T_FH. IL-21. Mostly involved in isotype switching in B-cells. T_reg. Promotes tolerance to antigens in other T-cells.

Cytokines induce the differentiation of naive CD4 T cells down distinct effector pathways

Similarly, we shall memorize the cytokines that commit primed T cells to different effector lineages.

These cytokines effect different members of the JAK/STAT pathway. Pattern of JAK/STAT activation leads to unique transcription factor + gene expression program for each effector type.

T_H_1. IFN-\gamma + IL-12. STAT1 + STAT4. T-bet. T_H_2. IL-4. STAT6. GATA-3. T_H_17. IL-6/IL-23. STAT3. ROR\gamma T_FH. IL-6. STAT3. Bcl-6. T_reg. IL-2. STAT5. FoxP3

CD4 T-cell subsets can cross regulate each other's differentiation through the cytokines they produce

Cytokines produced from some effectors can inhibit other effectors.

IL-4 inhibits T_H_1. IFN-\gamma inhibits T_H_2.

Regulatory CD4 T cells (T_regs) are involved in controlling adaptive immune responses

Can be created in the thymus or in the periphery.

Expression of FoxP3 is the classic marker. CTLA-4 / CD25 are surface markers.

General properties of effector T cells and their cytokines

Effector T-cell interactions with target cells are initiated by antigen-nonspecific cell-adehsion molecules

Antigen non-specific interaction of surface proteins LFA-1 / CD2 (which are expressed 2/4x higher than naive T-cells.

An immunological synapse forms between effector T cells and their targets to regulate signaling and direct the release of effector molecules

Effector T-cells and target cells form an immunological synapse / SMAC (supramolecular activation complex).

There is sometimes an inner and outer zone. The outer zone is where the useful immune activity occurs and the inner zone is where recycling of TCRs via ubiquitin taggin occurs.

Polarization is reorientation of internal organelles to direct effector molecules to a precise area:

• cortical actin cytoskeleton (at site of contact)
• MTOC
• Golgi apparatus

The effector functions of T cells are effected by the array of effector molecules they produce

Cytotoxins stored in cytotoxic granules Effector cytokines expressed de-novo

Cytokines can act locally or at a distance

TODO: table

T cells express several TNF-family cytokines as trimeric proteins that are usually associated on the cell surface