Lecture 10: Differentiation and Functions of CD4+ Effector Cells

**What are the three main functions of antigen presenting cells?

- engulf pathogens

- process pathogen antigen

- present antigens

What are the four main subsets of CD4+ helper T cells?

Th1

Th2

Th17

Tfh

What is the defining cytokine of Th1 cells?

IFN-gamma

What is the principal target cell of Th1 cells?

macrophages

What are the defining cytokines of Th2 cells? (what they make)

IL-4, IL-5, IL-13

What is the principal target cell of Th2 cells?

eosinophils (and mast cells).. and eventually Bcells to class switch to IgE production

What are the defining cytokines of Th17 cells? (what they make)

IL-17 and IL-22

**What is the principal target cell of Th17 cells?

neutrophils! (also monocytes) to attack extracellular bacteria and fungi

What are the defining cytokines of Thfh cells? (what they make)

IL-21 (and IFN-gamma or IL-4)

What is the principal target cell of Thfh cells?

B cells

What is the precursor cell for the Th1, Th2, Th17, and Treg cells?

naive CD4 T-cell

**IL-12, IL-18 promote differentiation of ______ lymphocytes

Th1

IL-4 promote differentiation of ______ lymphocytes

Th2

IL-6, IL-21 promote differentiation of ______ lymphocytes

Tfh

IL-6, TGF-Beta promote differentiation of ______ lymphocytes

Th17

TGF Beta/retinoic acid promote differentiation of ______ lymphocytes

Treg

IL-12 production by activated macrophages promotes _______

differentiation

Th1

__________ production by Th1 cells further activates macrophages to

secrete _______ ..........which promotes further differentiation of additional cells into the Th1 subtype

IFN-gamma

IL-12

______ cells develop in response to chronic forms of stimulation, such

as parasite infection and allergy. Such forms of antigen challenge usually have little macrophage activity, thus do not promote Th1 development.

Th2

__________ drives Th1 differentiation (transcription factor)

Tbet

__________ drives Th2 differentiation (transcription factor)

GATA-3

**__________ drives Th17 differentiation (transcription factor)

RoR-gamma(t)

**__________ drives Treg differentiation (transcription factor)

FoxP3

**In what context does TGF-Beta inhibit immune response?

in absence of infection, when IL-6 is secreted at low amounts & IL-10 is at higher amounts (from Th2) --> promotes Treg differentiation

**In what context does TGF-Beta promote an immune response?

in presence, onset of infection, and IL-6 is secreted in high amounts --> promotes Th17 differentiation

**What are the three signals required for CD4+ T cell Activation?

1) MHC molecule with antigen bound to TCR

2) Co-stimulatory signal with B7 (on APC) and CD28 (on Tcell)

3) Production of cytokines (like IL-6, IL-12, TGF-Beta) by APC to drive differentiation of T cell subtype

**What's the significance of CD40?

It is the receptor on activated macrophages, that when bound to CD40L on T cells, it will aid in macrophage activation

**What 3 major things happen when a macrophage is activated?

1) up-regulate receptors that will aid in recruiting/activating more macs (like CD40, MHC)

2) up-regulate lysozymal enzymes

3) up-regulate cytokine production that will also activate more macrophages

4) up-regulate oxygen free radicals

**______ is a principal mediator of the early innate immune response to

intracellular microbes and is a key inducer of CMI in the adaptive

phase of immunity to such pathogens.

IL-12

**What are three principal biologic actions of IL-12?

a. IL-12 stimulates IFN-gamma synthesis and secretion by Th1 T cells and NK cells.

b. In this role, IL-12 directs the differentiation of naïve CD4 T-cells to Th1 cells.

c. IL-12 enhances the cytolytic functions of differentiated CTLs.

**IL-12 is a critically important cytokine for _______________ responses (humoral/cell-mediated)

cell-mediated

**______ is a regulatory or inhibitory cytokine that is involved in the control (self-limiting) of innate and CMI IRs—focus on Macrophages

IL-10

**What subset of CD4 T cells are a key source of IL-10?

Treg cells, activated macrophages (negative

feedback) and Th2 cells

**What are the two key biologic actions of IL-10?

Inhibit the production and synthesis of IL-12 by

activated macrophages and dendritic cells.

Inhibit co-stimulator and MHC II expression by

activated macrophages and dendritic cells.

What are three main sources of IL-6?

macrophages, VECs, and fibroblasts

What is one of the major functions of IL-6 in acute inflammation/innate immune responses?

to stimulate acute phase protein

In adaptive responses _______ is produced by Th2 cells and has effects on effector B-cell proliferation and differentiation for antibody production

IL-6

IL-18 is homologous structurally to _______

IL-1

IL-18 is produced by ___________ in response to ______ and other microbial products

macrophages, LPS

What are the main functions of IL-18?

to stimulate IFN-gamma

production in both NK cells and Th1 cells (where it synergizes with IL-12)

_______: targets are T-cells and NK cells. Main function may be to influence differentiation of Th17 cells to produce IL-17 (discussed later).

IL-23

_______: targets are NK cells and T cells where it promotes Th1 differentiation and promotion of IFN-gamma secretion

IL-27

**______ is the major signal for a class switch to IgE in B-cells and is also the major stimulus for the differentiation of naïve CD4 T-cells to the Th2 subtype

IL-4

**What subset of CD4 T lymphocytes is the principal source of IL-4?

Th2

**What are the four principle biologic actions of IL-4?

1. Initiation of a class switch to IgE in B-cells

2. Stimulates differentiation of Th2 cells (mast cells?)

3. Promotes IgE and mast cell/eosinophil responses

4. Down-regulates macrophage responses

______ has structural similarity to IL-4 and it is produced by Th2 cells and some epithelial cells

IL-13

What is the main biologic effect of IL-13 on non-lymphoid cells?

mimics the inhibitory

effect of IL-4

_______ is an eosinophil activator and serves as a linkage between T-cell activation and eosinophil-mediated inflammatory responses

IL-5

What subset of CD4 T lymphocytes is the principal source of IL-5?

Th2

What are the two main biologic effects of IL-5?

stimulate the growth

and differentiation of eosinophils and to

activate mature eosinophils.

Initiate a class switch to IgA in effector B-cells

**___________ is the principal macrophage activating cytokine of the immune system and is the best example of a cytokine being involved in mechanisms of both innate and adaptive immunity

IFN-gamma

What subset of CD4 T lymphocytes is the principal source of IFN-gamma?

Th1 cells (and NK cells)

How does IFN-gamma affect MHC expression?

it enhances MHC I and II expression on APCs

IFN-gamma promotes differentiation of which CD4+ T helper subset?

Th1

IFN-gamma inhibits the differentiation, proliferation, and effector functions of naïve and effector/memory CD4 T-cells of the _____ subset

Th2

_________ inhibits the IL-4 mediated switch to IgE in B-cells

IFN-gamma

________ is involved in immune responses by inhibiting the activation and proliferation of lymphocytes and other leukocytes

TGF-Beta

**What subset of CD4 T lymphocytes is the principal source of TGF-Beta?

Treg cells (also macrophages and dendritic cells)

What are the 3 main biologic effects of TGF-Beta?

1. Inhibit the proliferation and differentiation of T-cells and the activation of macrophages....i.e., down-

regulate IRs.

2. Promote a class switch to IgA in B-cells in mice.

3. When secreted from dendritic cells in times without antigen stimulation, promotes Treg differentiation.