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