Lecture 8 - functional differentiation of effector T lymphocyte subsets in health and disease

What is the primary function of CD4⁺ T helper cells?

They act as central orchestrators of adaptive immunity, coordinating responses by activating B cells, cytotoxic T cells, macrophages, and shaping the immune environment through cytokine production.

What are the signature cytokines and key roles of Th1 cells?

• IFN-γ, TNF-β, IL-2

• Activate macrophages, help B cells produce opsonizing IgG1/IgG2a, enhance NK and CD8⁺ T cell responses.

• Fight intracellular pathogens (e.g., Mycobacterium leprae in tuberculoid leprosy).

• Involved in autoimmune diseases like MS and T1D.

What are the functions of IFN-γ and CD40L secreted by Th1 cells?

Activate macrophages to enhance microbicidal activity. In chronic infection, FasL and LTβ from Th1 induce apoptosis of infected macrophages to release pathogens for reuptake.

Which chemokine recruits macrophages to infection sites in Th1 responses?

CXCL2 — ensures macrophage accumulation at infected tissues.

What are the signature cytokines and key functions of Th2 cells?

• IL-4, IL-5, IL-13

• Activate eosinophils and mast cells, promote IgE switching.

• Combat extracellular parasites (e.g., helminths).

• Mediate allergic diseases like asthma, eczema.

What is the mechanism of Th2-mediated allergic responses?

Allergen (e.g., Der p 1) breaches epithelium → captured by DCs → presented to naïve T cells → Th2 differentiation → IL-4-driven IgE class switching → mast cell sensitization and degranulation upon re-exposure.

Which cytokines polarize naive CD4⁺ T cells into Th1, Th2, and Th17 subsets?

• Th1: IL-12, IFN-γ

• Th2: IL-4

• Th17: IL-6, IL-1β, TGF-β, IL-23

What are the defining features and cytokines of Th17 cells?

• IL-17A, IL-17F, IL-22

• Recruit neutrophils, induce IL-1β, MMPs, PGE2

• Fight fungi (Candida albicans) and extracellular bacteria

• Implicated in autoimmunity: psoriasis, RA, Crohn’s disease

Which cytokines and transcription factors drive pathogenic Th17 (pTh17) cell formation?

IL-23 and IL-1β, promote IL-17A, IL-17F, IFN-γ, GM-CSF expression.
Transcription factor: BHLHE40

How does IL-27 influence Th17 cells?

Promotes non-pathogenic Th17 (npTh17) that produce IL-17A, IL-22, IL-10 and help resolve inflammation.

Which biologics target the IL-23–Th17–IL-17 axis in inflammatory disease?

• IL-23 blockers: Ustekinumab, Guselkumab

• Th17 blockers: Iguratimod

• IL-17A/F blockers: Secukinumab, Ixekizumab

What are Tfh cells, their cytokine, and role?

• IL-21

• Support germinal center formation

• Help B cells with class switching and affinity maturation

• Involved in antibody-mediated diseases (e.g., SLE, RA)

What are the 3 key signals required for CD4⁺ T cell differentiation?

• TCR–MHC II binding (Signal 1)

• Co-stimulation (CD28–CD80/86) (Signal 2)

• Cytokine milieu (Signal 3) — determines Th subset fate

Which Jak–STAT pathways are involved in Th cell polarisation?

• IL-12 → STAT4 → Th1

• IL-4 → STAT6 → Th2

• IL-6, IL-23 → STAT3 → Th17

• IL-2 → STAT5 → Treg

What is the role of master transcription factors in Th subset identity?

• Th1: T-bet

• Th2: GATA-3

• Th17: RORγt

• Treg: Foxp3
  They promote subset-specific gene expression and repress alternative lineages.

What is T helper cell plasticity?

The ability of Th cells to change phenotype under certain cytokine environments — e.g., Th17 → Th1 or Treg → Th17 — contributing to immune flexibility or chronic inflammation.

What are the implications of Th cell plasticity in autoimmunity?

Plasticity allows flexibility but may contribute to chronic inflammation, dual-cytokine-producing cells (e.g., IL-17⁺ IFN-γ⁺), and loss of tolerance in autoimmune conditions.

How does citrullination contribute to RA pathogenesis?

Citrullinated peptides act as neoantigens due to post-translational modification → IL-17 production → ACPA generation → drives aggressive autoimmune responses.

Which immune markers are associated with severe RA?

• IL-17 production against citrullinated autoantigens

• ACPAs (anti-citrullinated protein antibodies)

What factors coordinate Th cell differentiation beyond cytokine signalling?

• TCR signal strength

• Master transcription factors

• Jak–STAT pathways

• Metabolic regulators

• Antigen modifications (PTMs)

How does the strength of TCR signalling influence Th cell fate?

Stronger or weaker Signal 1 can affect transcriptional programs, cytokine receptor expression, and downstream polarisation into different Th subsets.

What are post-translational modifications (PTMs) and how do they affect antigen presentation?

PTMs like citrullination, glycosylation, or methylation alter peptide structure and charge → affect MHC binding, TCR affinity, and influence Th polarisation.

How does citrullination contribute to antigenicity in RA?

PAD enzymes convert arginine to citrulline → creates neoantigens → triggers IL-17 responses and ACPA production → breaks tolerance → drives inflammation.

Which transcription factor is central to Th17 cell development?

RORγt — activated by STAT3 downstream of IL-6 and IL-23 signalling.

Which transcription factor is activated by IL-12 via STAT4 to promote Th1 polarisation?

T-bet

Which transcription factor is downstream of IL-4 and STAT6 in Th2 differentiation?

GATA-3

What are the functional differences between pathogenic and non-pathogenic Th17 cells?

• pTh17: IL-17A/F, GM-CSF, IFN-γ → pro-inflammatory, driven by IL-23/IL-1β

• npTh17: IL-10, IL-22, AHR → regulatory, driven by IL-27

What is the IL-23–Th17–IL-17 axis and why is it important in inflammatory disease?

It is a major driver of chronic inflammation in psoriasis, Crohn’s disease, and spondylitis.
IL-23 stabilizes Th17 cells and promotes IL-17 production → targeted by biologics.

Which biologic targets IL-17A to reduce inflammation in autoimmune diseases?

Secukinumab (also Ixekizumab, Netakimab)

What is the role of IL-21 in Tfh cell function?

Promotes B cell proliferation, class switching, and affinity maturation in germinal centers.

How does Jak–STAT signalling lead to transcriptional activation?

Jak kinases phosphorylate receptors → STATs bind, become phosphorylated → dimerize → translocate to the nucleus → induce gene transcription.

What are the Jak kinases and STAT proteins involved in Th subset polarisation?

• Jaks: Jak1, Jak2, Jak3, Tyk2

• STATs: STAT1–6
  Each cytokine activates specific Jak–STAT combinations for subset-specific gene expression.

What is the impact of epigenetic modifications in Th subset stability?

Transcription factors promote or suppress histone modifications and DNA accessibility, reinforcing Th subset-specific programs and suppressing alternative fates.

How do Th1 and Th2 subsets maintain their lineage identity?

Through mutual antagonism — e.g., T-bet represses GATA-3, and vice versa — supported by epigenetic feedback loops.

What is the clinical relevance of IL-17 in RA pathogenesis?

IL-17 is produced in response to citrullinated peptides, drives joint inflammation, and correlates with ACPA positivity and disease severity in RA.

What immune mechanism underlies the allergic response to house dust mite allergen (Der p 1)?

Der p 1 cleaves tight junctions → enters DCs → drives Th2 differentiation → IgE production → sensitization of mast cells → degranulation on re-exposure.

What distinguishes the immune pathology of tuberculoid vs. lepromatous leprosy?

• Tuberculoid: Th1-biased, IFN-γ-driven → localized, granuloma formation, bacterial control

• Lepromatous: Th2-biased, IL-4-driven → disseminated infection, poor macrophage activation