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

2. 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”

3. 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 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: ( /cyto.a.22520)

4. 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 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: ( /cyto.a.22520)

5. Mean, 90% and 95%
confidence bands

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

7. 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

8. Plasma cell
B effector cell
Mitochondria
Well developed ER

9. Nature 1998

10. Cj-TREC
Sj-TREC

11. TREC in Thymectomized vs Healthy Individuals

12. TREC in HIV+ vs Healthy Individuals

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

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

15. 2018

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

17. Chromatin modification occurs with aging in immune cells
2018

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

21. 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.

22. J Immunol 2012

23. PNAS 2011

25. Bocharov Model(feedback in proliferation – differentiation circuit)

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

27. N= Naïve T cells, C = pMHC complexes

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