Regulatory T cells

What are regulatory T cells?

immunosuppressive T cells with cytokine profiles distinct from Th1 and Th2 cells, specialised in suppression of immune response to both foreign antigens and self

Scurfy mice

FoxP3 mutation → severe autoimmunity AND impaired immune response

Basic mechanisms used by Tregs to repress immune response

• modulate APC maturation and function

• kill target cells

• disrupt metabolic pathways

• anti-inflammatory cytokines

Why do Th1 cells need suppressing?

if overexpressed they can induce autoimmunity eg IBD, MS, diabetes

Why do Th2 cells need suppressing?

can cause allergic response

Why do Th17 cells need suppressing?

induce inflammation

Result of increased Treg population

loss of cancer immunosurveillance, suppression of anti-tumour response, promotes cancer progression

How are relative proportions of a T cell population defined?

by affinities of T cell for self-peptide MHC

What polarising cytokines are required for differentiation into Tregs in the periphery?

IL10 and TGF beta

FoxP3

encodes Forkhead box P3 transcription factor, controls development of Tregs and their function

FoxP3 deletion/inactivation →

T cell hyperactivation eg immune dysregulation, polyendocrinopathy or enteropathy X-linked (IPEX) syndrome

What happens as a result of IPEX?

• 70% develop thyroiditis

• 90% develop diabetes

• high mortality at young age

IL10 secreted by Tregs

• inhibits IL12 production

• inhibits dendritic cells

• prevents CD28 phosphorylation

TGF beta secreted by Tregs

promotes iDO and inhibits IL2 production

IL35 produced by T cells

promotes conversion of naive T cells into Tregs

How do Tregs induce metabolic disruption via IL2?

Tregs have high CD25 (IL2 receptor) expression to compete with proliferating immune cells for IL2

How do Tregs induce metabolic disruption via cAMP?

Transfer cAMP to target cell, activating PKA to inhibit cell proliferation and differentiation

adenosine metabolic disruption (CD39 and 73)

CD39 converts ATP to AMP, CD73 converts it to extracellular adenosine → adenosine mediated immunosuppression of activated effectors expressing adenosine 2A receptor

How do Tregs induce cytolysis?

secrete granzymes and perforins to apoptose overactive effector cells

CTLA4

high B7 affinity and induces IDO which cleaves tryptophan and activates caspase 8

tryptophan

required for T cell activation

LAG3 (lymphocyte activation gene 3)

homologue of CD4 receptor, binds MHC II with higher affinity

nTreg phenotype

CD4+CD25+CD127(low)

nTreg associated markers

CTLA4+GITR+FoxP3+

nTreg suppression

contact-, granzyme B dependent, produces TGF beta

nTreg target cells

APCs and effector T cells

CD28 involvement with nTregs

thymic development and maintenance in periphery

Tregs in allergy

• inhibit Th migration and function

• inhibit allergen specific IgE, induce IgG4

• promote Breg IL10 production

• suppress eosinophil, basophil and mast cell activation

iTreg Tr1 and Tr3 in vivo role

mucosal immunity and inflammatory response

iTreg Th3 cells

induced from naive CD4 T cells by TGF beta, can be FoxP3+

how are iTreg Tr1s identified?

LAG3 and integrin alpha 2 subunit CD49b expression

Tregs in human pregnancy

increase in circulating Tregs during early pregnancy, peaking in the second trimester and tapering off towards birth

weak Th1 suppression in pregnancy

causes infertility/preeclampsia/miscarriage

How does colonisation with Clostridia increase Treg abundance?

SCFAs from bacterial fermentation of dietary fibre promote Treg expansion, and stimulate effectors to produce IL2 → Treg proliferation

How does B. fragilis induce Tregs?

produces polysaccharide A

Mtb infection and Tregs

expansion of Tregs parallel to effector T cell expansion, balancing pro vs anti inflammatory response

FoxP3+ Tregs in lung granulomas

recruited by Tb to downregulate inflammatory response