Lesson 20 – T-cell Differentiation and Memory

Initial activation signals 1 and 2 induces what?

• upregulation of prosurvival genes (Bcl-2)

• transcription of IL-2 and IL-2R genes

• the outcome is activation and robust proliferation (cell division), ultimately leading to the differentiation of memory cells and effector clonal cells

What regulates the differentiation of helper T-cell subesets

polarizing cytokines

Signal 3 - what cytokines are nearby when the T cell is activated?

APCs may bind PAMPS via PRRs, inducing cytokine secretion

What does engaging different PRRs result in

production of different cytokines

Viruses stimulate ___ to induce ___ subsets

Worms stimulate ___ to induce ___ subsets

• IL-12, TH1

• IL-4, TH2

What does TH1 regulate

immunity to intracellular bacteria and viruses

What does TH2 regulate

•immunity to parasitic worms

What does TH17 regulate

•immunity to extracellular bacteria and fungi

What does Treg do

•inhibitory in terminating immune responses and inhibiting autoimmunity.

What does Tfh do?

•regulate humoral immunity (B cells).

Helper T (T_H) subsets are distinguished by three properties, what are they?

1.a distinct set of polarizing cytokines that induces expression of:

2.a master gene regulator that regulates expression of:

3.a signature set of effector cytokines produced by that subset

What can cytokines achieve and how?

T_H1/T_H2 helper subset cross-regulation.

• IFN-γ from T_H1 responses inhibits IgG1/IgE class switching (a common T_H2-induced response).

• IL-4 from T_H2 responses inhibits production of IgG2a (a common T_H1-induced response).

• IL-10 from T_REG responses also inhibits T_H1 responses by suppressing the production of inflammatory mediators from APCs.

What does master regulators do?

•commit T cells to one subset or the other.

• T-Bet suppresses T_H2 pathway gene expression

• GATA3 suppresses T_H1 pathway gene expression

Activation in the presence of what forms the Th17 subset

IL-1β, IL-6, IL-23, and TGF-β

What is the master regulator RORγt and what does it do?

•The master regulator RORγt, an orphan steroid receptor, becomes active and differentiates activating T cells into this subset.

What does T_H17 produce

•T_H17 produce IL-17A, IL-17F, IL-21, and IL-22 that play a role in warding off fungal and extracellular bacterial infections.

What is excessive IL-17A production associated with?

excessive IL-17A production is associated with chronic inflammatory and autoimmune responses.

What were Peripheral T_REG (pT_REG) were formerly known as

•(induced) iT_REG cells

Peripheral T_REG (pT_REG) arise from where?

•They arise outside the thymus in the presence of TGF-β.

• TGF-β induces the FoxP3 master regulator, shifting activating cells into this subset.

What does pT_REG cells secrete

pT_REG cells secrete IL-10 and TGF-β to downregulate inflammation (by inhibiting APCs) and suppress other T-cell subsets

T_H17 and T_REG cross-regulation

•TGF-β is a key cytokine for differentiation of both subsets.

•T_REG cells dominate when only TGF-β is present.

•Addition of IL-6 is the “switch,” allowing RORγt to dominate and induce T_H17 subset differentiation instead.

•Thinking about the beneficial outcomes of each subset, a balance between the two is ideal.

•Normal state could favor development of suppressive pT_REG population to keep inflammation down.

•Inflammation from an infection (leading to IL-6 production) would stimulate more antibacterial T_H17 differentiation.

What were Follicular helper T (T_FH) cells are polarized by

•IL-6 and IL-21

T_FH cells aid B-cells in

the production of antibodies

IL-6 and IL-21 lead to activation of

•the Bcl-6 master regulator.

• This also inhibits T-Bet, GATA3, and RORγt expression.

• IL-4 and IL-21 are characteristic secreted cytokines that promote B-cell differentiation.

T_FH cells express CD40L, which is required for ___

they also express CXCR5 which is ___

• cognate B-cell help

• a receptor for a chemokine that attracts them to B-cell follicles

T_H9 cells produce IL-9, which helps to

expel parasitic worms and contributes to antitumor responses

IL-2, TGFβ, and IL-4 play roles in polarizing naïve T cells to

•T_H9 cells

Transcription factors IRF-4 and PU.1 drive

T_H9 differentiation

IL-6, IL-23, and TNF polarize naïve T cells to

T_H22 Cells subset by upregulating the AHR transcription factor.

The T_H22 effector cytokine is

•IL-22

Plasticity

helper T cells may not be irrevocably committed to a lineage early in differentiation.

• Early in differentiation, T_H subpopulations may be able to shift.

  • When exposed to IL-12, young T_H2 cells will produce IFN-γ.

  • Young T_H1 cells will produce IL-4 in T_H2 polarizing conditions.

  • Neither T_H1 nor T_H2 can adopt T_H17 or pT_REG traits.

• Fluidity among subsets makes definitive establishment of helper cell lineages difficult.

CD62L

•an adhesion protein that regulates naïve T-cell and central memory T-cell homing to secondary lymphoid organs

CCR7

a chemokine receptor that is high on naïve and central memory T-cells, regulates homing to secondary lymphoid organs

CD44

•highly expressed on effector and memory T-cells, increases in response to TCR-mediated activation signals

CD69

tissue-resident memory T-cells produce this C-type lectin that prevents immune cells from leaving tissue

Info about T_CM cells – central memory T cells

•reside in and travel between secondary lymphoid tissues

•live longer and divide more times than T_EM cells

•are rapidly reactivated by second Ag exposure

•can differentiate into several subset types depending on cytokine environment

Info about T_EM cells – effector memory T cells

•travel to and between tertiary tissues

•contribute better to first-line defenses

•shift right back into effector functions on second Ag exposure

Info about T_RM cells – tissue resident memory T-cells

permanent residents of previously infected tissue

•respond upon reinfection

•CD8⁺ T_RM found in multiple tissues such as skin and mucosa