1. Immunoregulation Jennifer Nyland, PhD Office: Bldg#1, Room B10
Phone:

2. Teaching objectives
To discuss regulation of immune responses including regulation by antibody, Tregs, and cytokines
To discuss some genetic factors influencing immunoregulation

3. 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

4. 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)

5. 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 +

6. Regulation by Ab Recognition:
Idiotype/anti-idiotype Ab interactions can stimulate or inhibit Ab responses
Ab blocking: Ab competes with B cells for Ag

7. Regulation by Ab Activation/Effector function:
Receptor cross-linking: Ag/Ab complexes binding to Fc receptors send inhibitory signal to Bs

8. Regulation by Ab Activation:
Ab/Ag immune complex bind complement (C3d), localize to APC via complement R → maintained source of Ag

9. 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

10. 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

11. 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

12. 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.

13. 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°

14. 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

15. The Th1/Th2 paradigm Th1 Th2 IFN-γ IL-4, IL-10, TGF-β Cell-mediated
immunity
Humoral
Immunity
inhibitory