Download Immunoregulation

Immunoregulation
Jennifer Nyland, PhD
Office: Bldg#1, Room B10
Phone: 733-1586
Email: [email protected]
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
Th1 response (IFNγ)
cytotoxicity
0.3
+++
1000
+
120
80
40
Th2 response (IL-4)
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
IFN-γ
inhibitory
Cell-mediated
immunity
Th1
Th2
Humoral
Immunity
inhibitory
IL-4, IL-10, TGF-β