Lecture 11, 12, 13

T cell subsets

why do we need different T cell subsets

diverse type of pathogens

different target sites

different target cells

cell types are classified based on

cytokines that induce differentiation

transcription factors that control gene expression

cytokines produced by the cells

cytokine production by T cells controls (helps) other cells of the immune response

overall T cell response diagram

important T cell subsets (223)

Th1 - intracellular pathogens, APC produced IL-12, T cell produces interferon gamma

Th2 - parasite, APC prodiuces IL-4, T cell stimulated to produce IL-5

Th17 - pathogen actvates APC, stimulated to produce IL-23, T cell stimulated to produce IL-17

JAK-STAT signalling

binding of cytokine to receptor = receptor dimerises

this brings receptor associated JAKs in close

JAKs phosphorylate each other on tyrosine residues

activated JAKs phosphorylate receptor

receptor phosphorylation creates binding sites for STATs

STATs bind, get phosphorylated by JAKs, then dissociate

STATs dimerise and translocate to nucleus

Th1 cells activation

IL-12 binds IL-12R and STAT4 dimerises

this causes production of interferon gamma and Tbet transcription factor

Th1 cells positive feedback

Tbet causes transcription of more interferon gamma, more Tbet and IL-12R

IFNgamma causes

increased expression of TLRs on APCs

increased MHC expression

increased chemokine secretion

increased macrophage activation

increased phagocytosis

produced by Th1 cells

Th1 cells overall diagram

Th2 overall diagram

Th2 cells stimulation

IL-4 binds receptor and causes STAT6 to dimerise

causes production of IL-4, IL-5 and IL-13 as well as GATA3 transcription factor

Th2 cells positive feedback

GATA3 causes feedback - get more IL-4,4,13 and GATA3 for more transcription and activation of this pathway

IL-4

activates B cells

enhances IgG and IgE production

inhibits activated macrophages

suppress proinflammatory mediators (IL-1 and TNF)

produced by Th2 cells

Th2 cells and antibody

IL-4 stimulates B cells to make IgE

IL-5 activates mast cells and basophils

IL-13 stimulates mucus production to try and rid the body of the dead parasite

also associated with atopy and allergy

Th17 cells overall diagram

Th17 step 1

through IL6 binding receptor which causes STAT3 to dimerise and TGFbeta binding its receptor as well

causes production of IL-17, IL-21 and its receptor as well as RORgamma transcription factor

Th17 step 2

IL-21 binding its receptor also causes STAT3 to dimerise which causes transcription of IL-17, IL-21 and IL-23 and IL23R

also IL-22 which helps to repair epithelial cells

Th17 cells step 3

IL23 binds its receptor also causin STAT3 to dimerise and produces IL-17 for stability and maintanence

IL-17

promotes recruitment of neutrophils

activates innate immune cells

enhances B cell functions

induces pro-inflammatory cytokines

can promote production of IL-10 to reduce inflammation

produced by Th17 cells

cytokines produced by IL-17 cells

IL-17 - recruits neutrophils and promotes inflammation

IL-22 - stimulate epithelial cells to produce anti-microbial peptides

IL-23 - promotes maintenance of Th17 phenotype

also associated with chronic inflammatory diseases such as MS and IBD

why Th17 cells more complicated

these cells are highly regulated because they have such toxic effects on the body so have to be sure it is needed before activating this pathway

other types of T cell subsets

Th9, Th22, Tfh cells

Th9 cells

transcription factor PU.1

polarised by IL-4 and TGFb, close to Th2 cells

produce IL-9

roles in parasite response, inflammation

Th22 cells

transcription factor AHR

polarised by IL-6 and TNF, close to Th17 cells

produce IL-22

epithelial repair and barrier function

Tfh cells

transcription factor Bcl-6

polairsed by Il-6 and IL-21

produce lots of cytokines, germinal centre - support antibody class switching

Tfh and B cell diagram

defining T cell subsets - transcription factors

Not super clear cut - where one is expressing something and nothing else is - lots of expression between the different types of cells

Have to think about how you would define what you think is a Th1 cell, Th2 cell etc

Makes sense that these are a bit blurred in an immune response as you need lots of different cells to be doing different things and the response is also changing

T cell subset overlap

Not looking at what is being produced

Get clusters of cells with similar expression and can class these into subsets

Tfh do lots so lots of overlap

Th2 and Tregs quite separate

If you only look at one thing they look different, but when you start looking at lots of different things you see they have similar things expressed

regulatory T cells overview

immune responses to pathogens cause damage

need to control the scope and size of the immune response

autoreactive cells escape regulation in development - need to control autoimmune responses

types of Tregs

thymic Tregs come from the thymus and are already a Treg

induced Tregs develop from niave T cells in the periphery in response to antigen activation and cytokine signals
Tregs are a type of T cell subset

T cells in thymus can differentiate into

CD8 cells

CD4 cells

CD4 reg

Tregs and CD24