Chapter 7: T-Cell Mediated Adaptive Immunity

T Cell Priming

Naive T cells circulate in blood and lymph, interact with antigen-presenting cells (APCs) in secondary lymphoid tissues that present a varitery of peptides on MHC molecules, TCR and MHC-peptide complex interact leading to T cell activation, activated T cells differentiate into effector T cells

Where Naive T cell Activation Occurs

in a draining secondary lymphoid tissue when professional APCs have migrated

T Cell Homing

occurs through chemokines and cell-adhesion molecules, chemokines signal to the cell that it must migrate to a particular location, adhesion molecuels allow the cell to attach to a specific tissue

Cell Signaling

naive T cells move out of the circulatory and lymphatic systems into secondary lymphoid tissue

Cell Signaling Lymph Nodes

dendritic cells and stromal cells secrete chemokines CCL19 and CCL21; they establish a chemokine gradient by binding to endothelial cells of the venule

Cell Signaling: CCR7

binds to CCL19 and CCL21, allows them to bind the endothelial cells and begin migration

T Cell Migration into Secondary Lymphoid Tissue Steps

Rolling Adhesion, tight binding, diapedesis, migration

T Cell Migration into Secondary Lymphoid Tissue Steps: Rolling Adhesion

L-selectin (T cell) binds to CD34 and GlyCAM-1 adhesion molecules on the endothelial cell surface, T cell then binds to the endothelial cells via LFA-1 binding to ICAM-1 and ICAM-2

T Cell Migration into Secondary Lymphoid Tissue Steps: Migration

T cells that are not activated by an interaction with an MHC peptide complex on an APC exit the secondary lymphoid tissue and re-enter the lymphatic system through an efferent lymphatic vessel; movement back into circulation is mediated by sphingosine-1-phosphate

How T Cells are Activated: Interactions

Interaction of TCR and MHC peptide complex on APC, interaction between CD28 on T cell and a B7 molecule on the APC; B7 molecules are only expressed on the surface of professional APCs when infection is present

What Induces B7 Expression

PAMP receptors, including TLRs; only expresssed on the surface of professional APCs when infection is present

Immunological Synapse

interaction between the TCR and MHC peptide complex leads to the formation of this between the cells

Immunological Synapse Components

TCR and MHC peptide complex, costimulatory signaling molecules, CD4/CD8 and MHC PC, other cell adhesion molecules which allow a seal to form between the two cells

Interleukin-2 Role

IL-2 production and IL-12 production

IL-2 Production

induced by formation of an immunological synapse, requires a costimulatory signal via CD28; Only activated T cells will be able to bind and respond to IL-2 that is produced by a newly activated naive T cell when signaled through CD28-B7 expression 

IL-2 Receptor Expression Low Affinity

Naive T cells express a low affinity IL-2 receptor made of two protein subunits (B and y); Activated T cells synthesize an alpha subunit that interacts with B and y subunits to form a high affinity IL-2 receptor

IL-2 Receptor High Affinity

Activated T cells synthesize an alpha subunit that interacts with B and y subunits to form a high affinity IL-2 receptor

IL-12 Production

regulated through destabilization of the mRNA responsible for protein translation; Signal transduction activated through CD28 employs mechanisms taht work to stabilize the IL-2 mRNA 

Costimulatory Signal

CD28 and B7, important to activation of T cells that recognize self-antigen

Costimulatory Signal B7

Naive T cells that bind tightly to an APC presenting self-peptides do not receive a costimulatory signal (B7) because there is no infection present; T cell is not activated, enters anergy; negative selection in the periphery prevents an autoimmune response

Anergy

nonresponsive and cannot enter clonal expansion

How Effector T Cells Utilize Cytokines

Alter immune cell behavior or destroy damaged or infected cells; T cell function occurs through cytokine/cytokine receptor activity

Janus Kinases (JAKs)

Cytokine receptors have a cytoplasmic tail associated with Janus Kinases (JAKs); Cytokine binding to its receptor causes JAK kinase activation

Activated JAKs

Activated JAKs phosphorylates STAT proteins, Act as transcription factors to induce gene expression 

TH1 Helper T Cells

activate macrophages

TH2 Helper T Cells

activate B cells and granulocytes in response to multicellular parasites

TFH Helper T Cells

activate B cells for immunoglobulin production (antibody production) to combat extracellular pathogens, secrete IL-21 and IL-4 to promote B-cell activation and isotype switching

Cytotoxic T Cells

primarily work to destroy infected cells

Memory T Cells

typically remain close to where they were produced to monitor for the return of the antigen

CD4 Effector T Cells

IL-12 and IFN-y activates CD4 T cells to differentiate into TH1 helper T cells; Produce IFN-y to activate macrophages and promote differentiation of more TH1 helper T cells; some migrate to a primary follicle to differentiate into TFH cells

TH17 Helper T Cells

Primarily activate neutrophils so they can target extracellular pathogens

Production of CD8 Effector T Cells

require a stronger costimulatory signal to become activated than CD4; only dendritic cells produce B7 surface molecules; interact successively with the CD4 T cells stimulating enhanced B7 exprssion on an APC, which then serve as a costimulatory signal for naive CD8 T cells

Effector T Cells and Costimulation

do not require; cytotoxic T cells can kill any cell infected with an intracellular pathogen, helper T cells can be activated by macrophages and B cells at a site of initial infection

Cytotoxic T Cells Function: Lytic Granules

destroy target cells, carry lytic granules that contain cytotoxins (specialized proteins); lytic granules form and fill with cytotoxins after naive T CD8 T cell is activated

Cytotoxic T Cell Function: Granule Secretion

focus granule secretion at a specific target cell, causing its destruction; Cytotoxic T cells must prevent release of target cell contents to avoid damaging host tissues

Cytotoxic T Cell Function: Apoptosis

Creating pores in the target cell membrane via perforin, granulysin, and granzymes; Expressing the protein Fas ligand that binds to Fas on the target cell, recruiting apoptotic proteins to the plasma membrane

TH1 Helper T Cell Function

release cytokines that activate macrophages that present antigens via MHC class II molecules; leave the secondary lymphoid tissue and move to infection site; form an immunological synapse with the presenting macrophage forming a conjugate pair

Macrophage Activation by TH1 T Cells: Two Signals for Activation

IFN-γ secreted by TH1 cells; T-cell surface molecule CD40 ligand (CD40L), Binds to CD40 on macrophage surface; increase expression of CD40 and TNF-a receptors, macrophages produce TNF-a, acts synergistically to enhance activation

TH1 Helper T Cells Function: Synthesis

synthesis of IFN-y and CD40L; however, TH1 helper T cell must remain in contact with the macrophage to continue expression of these molecules 

TH1 Helper T Cell Macrophage Activation: Directing

The production and location of CD40L on its surface; the direction in which it secretes IFN-y

TH2 Helper T Cells Function: Cytokines

Release cytokines such as IL-5 to activate granulocytes; also secretes IL-4, which activates B cells to express the immunoglobulin isotype IgE

TH2 Helper T Cell Function: Granulocytes

Used by granulocytes such as mast cells for pathogen recognition; Leads to subsequent inflammatory response that works to expel pathogens 

Follicular Helper (TFH) T Cells Function Germinal Centers

Aid in the activation and differentiation of B cells in germinal centers of secondary lymphoid tissue; Interact with antigen-presenting B cells that have migrated from a site of infection to a draining secondary lymphoid tissue

TFH T Cells Function: Recognition

If antigen is recognized by a TFH cell, it forms a conjugate base pair with the B cell; Activated B cells and T cells expand and form a primary focus in the secondary lymphoid tissue 

TFH Helper T Cells Function: Response to Pathogen

TFH cell first responds through the synthesis of CD40L that binds to CD40 on the B-cell surface; Prompts B cell division 

TFH Helper T Cell Function: Cytokines

secreted IL-4 promotes clonal expansion; Other cytokines produced by the TFH cell including IL-21 promote B-cell differentiation into plasma cells

TFH17 Helper T Cells Differentiation

CD4 T Cells differentiate into these, subset mainly driven by cytokines TGF-B and IL-6

TFH17 Helper T Cell Function: Neutrophils

Stimulate neutrophils to clear extracellular bacteria and fungi; Activated early in the adaptive immune response; allows for clearnace of an extracellular bacterial or fungal infection

TFH17 Helper T Cell Function: Cytokine

Major cytokine produced is IL-17; Induces expression of chemokines that recruit neutrophils to a site of infection 

Regulatory T Cell Function

T_regs modulate the immune response, maintain tolerance to self-antigens and prevent autoimmunity; most use transcription factor Foxp3 to perform immune response suppression

Regulatory T Cell Development

A subset of Tregs develops to regulate effector CD4 and CD8 cells by suppressing activation

Natural Regulatory T Cells

Develop from autoreactive T cells in the thymus 

Regulatory T Cells Function: Infection Control

Tregs deactivate helper T cells and cytotoxic T cells once an infection is controlled; Peripheral or induced regulatory T cells develop at the site of an immune response 

Natural Killer T Cell Function

develop in the thymus; express a specific a:B TCR that recognizes a glycolipid presentd by a CD1d molecule; they use this glycolipid TCR interaction to combat various types of bacterial infections