Immunoregulation

Jennifer Nyland, PhDOffice: Bldg#1, Room B10

Phone: 733-1586Email: jnyland@uscmed.sc.edu

Teaching objectives

• To discuss regulation of immune responses including regulation by antibody, Tregs, and cytokines

• To discuss some genetic factors influencing immunoregulation

Regulation of immune responses

• Magnitude of immune response determined by:– Ag-driven activation of lymphocytes– Negative regulatory influences that prevent or

dampen response

• Regulatory mechanisms act at all phases of immune response– Recognition– Activation– Effector function

Regulation in response to Ag

• Recognition: – in absence of co-stimulation → anergy (inability to

respond)• Activation: – with CTLA-4 engagement of CD80/CD86 → down

regulation of Ts (dampens activation)• Effector function:– Too much Ag → tolerance (induced state of

unresponsiveness)

Regulation in response to Ag

• Dose (and route) of Ag exposure- see Ag lecture

Virus dose (pfu)

Antiviral cytotoxicity

Th1 response (IFNγ) Th2 response (IL-4)

0.3 +++

1000 +

120 80 40 0 40 80 120

Regulation by Ab

• Recognition:– Idiotype/anti-idiotype

Ab interactions can stimulate or inhibit Ab responses

– Ab blocking: Ab competes with B cells for Ag

Regulation by Ab

• Activation/Effector function:– Receptor cross-linking:

Ag/Ab complexes binding to Fc receptors send inhibitory signal to Bs

Regulation by Ab

• Activation: – Ab/Ag immune complex bind

complement (C3d), localize to APC via complement R → maintained source of Ag

Regulation by cytokines

• Cytokines are positive or negative regulators– Act at many stages of immune response– Dependent on milieu• Other cytokines and receptors

– Regulate the type and extent of immune response generated

Regulation by Tregs

• Regulatory Ts (Tregs) do not prevent initial T activation– Inhibit sustained response– Prevent chronic and potentially damaging

responses

• Do not have characteristics of Th1, Th2, Th17• Suppress Th1 and Th2 responses

Regulation by Tregs

• Types of Tregs: Naturally arising– Thymus gives rise to CD4+CD25+Foxp3+ = Treg• CD25 = part of IL-2R• Foxp3 = transcription factor, defects → autoimmune

and inflammatory disease

– Suppress in cell-cell dependent manner• Mechanism unknown

Regulation by Tregs

• Types of Tregs: induced Tregs– In the periphery some Ts induced to Treg– Requires Ag, IL-10, or TGF-β• IL-10: CD4+ CD25+ Foxp3- these are Tr1• TGF-β: CD4+ CD25+ Foxp3+• Ag: CD4+ CD25- Foxp3-

– Suppress by secretion of:• Tr1 by IL-10• Induced Treg by TGF-β• T effector memory cells by IL-2, IFN-γ, etc.

Regulation by Tregs

• Types of Tregs: CD8+ Tregs (CTL2 cells)– release a spectrum of cytokines similar to Th2

cells: IFN-γ, IL-6, IL-10– Differentiation affected by CD4+ cytokine profile,

Ag, and IL-10• CD8+ Foxp3+

– Suppress in a cell-contact dependent manner• downregulation of co-stimulatory molecules on APC →

tolerance• Primed by CD4+ during 1°, suppress during 2°

Genetic factors

• MHC-linked genes control response to infection– Certain HLA haplotypes are associated with

responders/nonresponders, susceptibility/resistance

• Cytokine and chemokine polymorphisms– Primarily in receptor genes

• Non-MHC genes– Example, regulation of macrophage activity

The Th1/Th2 paradigm

Th1 Th2

IFN-γ

IL-4, IL-10, TGF-β

Cell-mediatedimmunity

HumoralImmunity

inhibitory

inhibitory