Theoretical Immunology: Aging

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Presentation transcript:

Theoretical Immunology: Aging Alan S Perelson Theoretical Biology & Biophysics Los Alamos National Laboratory

The Immune System Changes as we Age Lymphocyte counts are high when we are born and then fall as we age. Initially T lymphocytes are “naïve” and after they are exposed to cognate antigen and respond become memory cells. Thus, we are born with high levels of naïve cells that decrease with age, while numbers of memory cells increase with age. Levels of antigen-specific lymphocytes change with antigenic experience – “learning”

Lymphocytes subsets reference values in childhood Lymphocyte subsets' trend with age (n × 106/L). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Lymphocytes subsets reference values in childhood, Cytometry Volume: 87, Issue: 1, Pages: 81-85, First published: 06 August 2014, DOI: (10.1002/cyto.a.22520)

Lymphocytes subsets reference values in childhood naive memory Lymphocyte activation markers' trend with age (%). CD3+ HLA‐DR+ and CD3+ CD25+ are expressed as a percentage of the total lymphocytes (gate CD45/SS). CD3+ TCRγδ+ and CD3+ CD4− CD8− are expressed as a percentage of the total T lymphocytes (gate CD3/SS). CD4+ CD45RA+ and CD4+ CD45RO+ are expressed as a percentage of T helper lymphocytes (gate CD4/SS). CD3+ CD38+ and CD19+ CD38+ are expressed as a percentage of the two populations (gate CD3/SS and CD19/SS, respectively). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Lymphocytes subsets reference values in childhood, Cytometry Volume: 87, Issue: 1, Pages: 81-85, First published: 06 August 2014, DOI: (10.1002/cyto.a.22520)

Mean, 90% and 95% confidence bands

Small resting lymphocyte Cell is mostly nucleus Very little cytoplasm No mitochondria present No endoplasmic reticulum

Large lymphocyte - lymphoblast More cytoplasm created Mitochondria present Stimulation of a naïve cell Turns on hundreds - thousands of genes that cause structural changes that remain as cell transitions into a “memory” cell

Plasma cell B effector cell Mitochondria Well developed ER

Nature 1998

Cj-TREC Sj-TREC

TREC in Thymectomized vs Healthy Individuals

TREC in HIV+ vs Healthy Individuals

Borghans De Boer Nat Med 2000 Thymus Naive T-cell pool: N s(t) p 2012

Thymus changes with age George and Ritter, Thymic involution and ageing. Immunol. Today 1996.

2018

Age at which T cells leave thymus affects their response to infection 2018

Chromatin modification occurs with aging in immune cells 2018

Immune Memory Although memory cell numbers increase with age, distribution of memory cells specific for different antigens can change as new antigens are encountered.

Number of naïve cells specific to any given epitope is generally very small In mice the number of precursors can vary from a few cells to thousands of cells. The size of the precursor pool and how they expand can influence immune response success.

J Immunol 2012

PNAS 2011

Bocharov Model(feedback in proliferation – differentiation circuit)

Model Parameters (n=15) Simplified Model (B, n=10)

N= Naïve T cells, C = pMHC complexes

Mayer et al., Competition for presented Ag Model also fits kinetics of T cell expansion; here shown for 2 different precursor frequencies