Biology of Immune Aging
Jorg J. Goronzy
Stanford University
Immune deficiency • Increase morbidity and mortality from infections • Poor vaccine responses • Cancer
Autoimmunity • Autoantibody production • Polymyalgia rheumatica • Giant cell arteritis • Rheumatoid arthritis
Chronic inflammation • Coronary artery disease • Alzheimer’s disease • Osteoporosis • Frailty
Immune Aging
Aging and the Immune System
Intrinsic immune aging threats
• Declining regenerative capacity, increased cell loss
• Failure of homeostatic mechanisms Imbalance of functional cell subsets Contraction in T and B cell receptor diversity
• Failure in cell proliferation - Cellular senescence
• Failure in cell activation
• Induction or repression of gene expression Differentiation Chronic stimulation and proliferation Epigenetic changes
Aging and the Immune System
Extrinsic immune aging threats
• Declining barrier function
• Chronic infections (CMV)
• Cumulative antigenic experience over lifetime
• Tissue injury and repair
0 1 2 3 4 5 6
0 20 40 60 80 100
Age (years)
HPC
(cel
ls/µ
L)
Decline in peripheral hematopoetic progenitor cells
Rossi et al., Dorshkind et al.
Imbalanced lineage commitment of HPC
Pro-inflammatory
• No reduction in neutrophil or monocyte numbers
• Increased serum IL-6, IL-18, TNF
• Constitutive activation of signaling pathways (STAT)
Anti-inflammatory
• Reduced activation-induced neutrophil chemotaxis, phagocytosis, oxidative burst
• Reduced TLR and cytokine responses in monocytes
? Chronic innate activation due to • Defective barrier function • Defective adaptive immunity • Degenerative tissue damage
? Defective innate responsiveness • Cell-intrinsic defects (e.g. physical membrane
properties) • Attenuation to inflammatory environment (e.g.
induction of negative regulatory SOCS pathways)
Estimates of T-cell kinetics in humans Cell type
CD4
CD8
Pool size (no. of cells)
2 × 1011
1 × 1011
T1/2 (days)
87
77
Daily production rates (cells/day)
~1.3 × 109
~0.8 × 109
~2.1 × 109
= ~1% of the pool
The T-cell compartment – A highly dynamic system
Hellerstein, M. et al. Nat Med. 1999 Jan;5(1):83-9.
Age-dependent decline in thymic output
Aging and T Cell Homeostasis
P=0.002
P<0.001
P=0.035
Naylor, K et al. J Immunol. 2005 Jun 1; 174(11):7446-52
Hakim, FT et al. J Clin Invest. 2005 April 1; 115(4): 930–939
Age-dependent decline in thymic output
Thymus
Increased homeostatic T cell proliferation
Decline in thymic T cell generation
Naive
Memory
Surh, Sprent. Immunity 2008, 29, 848
Lymphopenia-induced proliferation • Response to acute lymphopenia • Response to self-MHC • Slow turnover • Transition into memory-like cells
Chronic lymphopenia-induced proliferation • Response to chronic lymphopenia • Response to microbial antigen • Fast turnover • Differentiation into effector cells
Cytokine-induced proliferation • Response to elevated cytokines • Response to self-MHC • Fast turnover • Transition into memory or effector T cells
Mouse Models of Homeostatic Proliferation
Thymus
Increased homeostatic T cell proliferation
Decline in thymic T cell generation
Naive
Memory
Peripheral selection of T cells
• Recognizing self with above average affinity
• Recognizing neoantigens (e.g. citrullination)
• Lowered T cell receptor activation thresholds
• Hyperresponsive to growth factors
• Differentiation into memory-
like or effector T cells
• Oligoclonal expansion
• Increased autoreactive
potential
Aging and T Cell Telomeres
CD
4 na
ive
T ce
lls (%
of t
otal
CD
4)
0
20
40
60
80
100
P<0.001
20-40 years 60-80 years
CD4
Robustness of the CD4 T cell compartment to homeostatic failure
CD
8 na
ive
T ce
ll (%
of t
otal
CD
8)
0
20
40
60
80
100
P<0.001
CD8
Czesnikiewicz-Guzik M et al. Clin Immunol. 2008 Apr;127(1):107-18
Young memory
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
T cell receptor β-chains (%)
75-80 years 60-65 years 25-30 years
< 0.05
> 20.0
0.2 - 0.05
1.0 - 0.2
5.0 - 1.0
20.0 - 5.0
Freq
uenc
y ( 1
/n x
10-
6 )
Naive CD4 T cells
Naylor, K et al. J Immunol. 2005 Jun 1; 174(11):7446-52
CD
4 su
bset
s (%
CD
4 m
emor
y ce
lls)
0
20
40
60
80
100
CM EM CD45RA Effector
CD
8 su
bset
s (%
CD
8 m
emor
y ce
lls)
0
20
40
60
80
100
CM EM CD45RA Effector
P=0.01
P<0.001 P<0.001
20-40 years 60-80 years
CD4 and CD8 T memory subsets
Czesnikiewicz-Guzik M et al. Clin Immunol. 2008 Apr;127(1):107-18
cytotoxicity
CD40L
CD28
T-cell antigen receptor
CD45RA effector T cells
NKG2D
KIR
Perforin
high cytokine production
CX3CR1
Clonally expanded Self-reactive
Engagement of activating co-receptors Antigen-independent activation
Clonally expanded Specific for latent viruses Lack of clonal exhaustion
Chronic tissue inflammation
Autoimmunity
Terminally Differentiated CD45RA Effector T Cells
Aging and DNA Damage in T Cells
Age (years) Age (years)
Con RA
Memory (CD4+CD45RA-CCR7-) Naïve (CD4+CD45RO-CCR7+)
;;;;;;;;;
0
4
8
12
16
0 20 40 60 80
Con RA
0
10
20
30
0 20 40 60 80
Con RA
Shao et al, JEM, 2009
Preferential generation of myeloid cells
Increased constitutive activation • defective barrier • increased systemic cytokines • degenerative tissue damage • viral reactivation due to defective adaptive immunity • DNA damage
Peripheral selection of pro-inflammatory T cells • self-reactive • low TCR threshold • increased cytokine sensitivity • differentiated into memory-like or effector T cells with homeostatic proliferation in the absence of exogenous antigen • clonally expanded end-differentiated effector T cells