CD4+/CD8+ ratio
{{Short description|Ratio of cells in immunology}}
The CD4+/CD8+ ratio is the ratio of T helper cells (with the surface marker CD4) to cytotoxic T cells (with the surface marker CD8). Both CD4+ and CD8+ T cells contain several subsets.{{cite journal | vauthors=Golubovskaya V, Wu L | title=Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy | journal=Cancers | volume=8 | issue=3 | pages=e36 | year=2016 | doi = 10.3390/cancers8030036 | pmc= 4810120 | pmid=26999211| doi-access=free }}
The CD4+/CD8+ ratio in the peripheral blood of healthy adults and mice is about 2:1, and an altered ratio can indicate diseases relating to immunodeficiency or autoimmunity.{{Cite book|title=Kuby Immunology|last1=Owen|first1=Judith|last2=Punt|first2=Jenni|last3=Stranford|first3=Sharon|publisher=W. H. Freeman and Company|year=2013|location=New York|pages=40}} An inverted CD4+/CD8+ ratio (namely, less than 1/1) indicates an impaired immune system.{{cite journal | vauthors=McBride JA, Striker R | title=Imbalance in the game of T cells: What can the CD4/CD8 T-cell ratio tell us about HIV and health? | journal=PLOS Pathogens | volume=13 | issue=11 | pages=e1006624 | year=2017 | doi = 10.1371/journal.ppat.1006624 | pmc=5667733 | pmid=29095912 | doi-access=free }}{{cite journal | vauthors=Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, Ligotti ME, Zareian N, Accardi G | title=Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention | journal=Frontiers in Immunology | volume=10 | pages=2247 | year=2019 | doi = 10.3389/fimmu.2019.02247 | pmc=6773825 | pmid=31608061 | doi-access=free }} Conversely, an increased CD4+/CD8+ ratio corresponds to increased immune function.{{cite journal | vauthors=Bradshaw PC, Seeds WA, Curtis WM | title=COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm | journal=Oxidative Medicine and Cellular Longevity | volume=2020 | pages=6401341 | year=2020 | doi = 10.1155/2020/6401341 | pmc=7519203 | pmid=33014275| doi-access=free }}
Obesity and dysregulated lipid metabolism in the liver leads to loss of CD4+, but not CD8+ cells, contributing to the induction of liver cancer.{{cite journal | vauthors=Tran NL, Sitia G | title=New players in non-alcoholic fatty liver disease induced carcinogenesis: lipid dysregulation impairs liver immune surveillance | journal=Hepatobiliary Surgery and Nutrition | volume=5 | issue=6 | pages=511–514 | year=2016 | doi = 10.21037/hbsn.2016.11.08 | pmc=5218901 | pmid=28124011 | doi-access=free }} Regulatory CD4+ cells decline with expanding visceral fat, whereas CD8+ T-cells increase.{{cite journal | vauthors=Krüger K, Eder K, Ringseis R | title=Immune and Inflammatory Signaling Pathways in Exercise and Obesity | journal=Am J Lifestyle Med | volume=10 | issue=4 | pages=268–279 | year=2014 | doi = 10.1177/1559827614552986 | pmc= 6125063 | pmid=30202282}}
Decreased ratio with infection
A reduced CD4+/CD8+ ratio is associated with reduced resistance to infection.{{cite journal | vauthors=Yin Y, Qin J, Dai Y, Zeng F, Pei H, Wang J | title=The CD4+/CD8+ Ratio in Pulmonary Tuberculosis: Systematic and Meta-Analysis Article | journal= Iranian Journal of Public Health | volume=44 | issue=2 | pages=185–193 | year=2015 | pmc = 4401876 | pmid=25905052}}
Patients with tuberculosis show a reduced CD4+/CD8+ ratio.
HIV infection leads to low levels of CD4+ T cells (lowering the CD4+/CD8+ ratio) through a number of mechanisms, including killing of infected CD4+. Acquired immunodeficiency syndrome (AIDS) is (by one definition) a CD4+ T cell count below 200 cells per μL. HIV progresses with declining numbers of CD4+ and expanding number of CD8+ cells (especially CD8+ memory cells), resulting in high morbidity and mortality.{{cite book|last=Kumar|first=Vinay|title=Robbins Basic Pathology|year=2012|isbn=9781455737871|page=147|publisher=Elsevier Health Sciences |url=https://books.google.com/books?id=jheBzf17C7YC&pg=PA147|edition=9th}} When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections. Declining CD4+/CD8+ ratio has been found to be a prognostic marker of HIV disease progression.{{cite journal | vauthors=Bruno G, Saracino A, Monno L, Angarano G | title=The Revival of an "Old" Marker: CD4/CD8 Ratio | journal= AIDS Reviews | volume=19 | issue=2 | pages=81–88 | year=2017 | url=https://www.researchgate.net/publication/313553795 | pmid=28182620}}
COVID-19
{{Confusing section|date=June 2021}}
In COVID-19 B cell, natural killer cell, and total lymphocyte counts decline, but both CD4+ and CD8+ cells decline to a far greater extent.{{cite journal | vauthors=Huang W, Berube J, McNamara M, Saksena S, O'Gorman M | title=Lymphocyte Subset Counts in COVID-19 Patients: A Meta-Analysis | journal=Cytometry Part A | volume=97 | issue=8 | pages=772–776 | year=2020 | doi = 10.1002/cyto.a.24172 | pmc=7323417| pmid=32542842 }} Low CD4+ predicted greater likelihood of intensive care unit admission, and CD4+ cell count was the only parameter that predicted length of time for viral RNA clearance.
Decreased ratio with aging
A declining CD4+/CD8+ ratio is associated with ageing, and is an indicator of immunosenescence.{{cite journal | vauthors=Kalathookunnel Antony A, Lian Z, Wu H| title=T Cells in Adipose Tissue in Aging | journal=Frontiers in Immunology | volume=9 | pages=2945 | year=2018 | doi = 10.3389/fimmu.2018.02945 | pmc=6299975 | pmid=30619305 | doi-access=free }} Compared to CD4+ T-cells, CD8+ T-cells show a greater increase in adipose tissue in obesity and aging, thereby reducing the CD4+/CD8+ ratio. Amplication of numbers of CD8+ cells are required for adipose tissue inflammation and macrophage infiltration, whereas numbers of CD4+ cells are reduced under those conditions.{{cite journal | vauthors=Catalán V, Gómez-Ambrosi J, Rodríguez A, Frühbeck G| title=Adipose tissue immunity and cancer | journal=Frontiers in Physiology | volume=4 | pages=275 | year=2013 | doi = 10.3389/fphys.2013.00275 | pmc=3788329 | pmid=24106481| doi-access=free }} Antibodies against CD8+ T-cells reduces inflammation associated with diet-induced obesity, indicating that CD8+ T-cells are an important cause of the inflammation. CD8+ cell recruitment of macrophages into adipose tissue can initiate a vicious cycle of further recruitment of both cell types.{{cite journal | vauthors=Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R | title=CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity | journal=Nature Medicine | volume=15 | issue=8 | pages=914–920 | year=2009 | doi = 10.1038/nm.1964 | pmid=19633658| s2cid=5222216 }}
Elderly persons commonly have a CD4+/CD8+ ratio less than one. Obesity is associated with a reduced CD4+/CD8+ ratio,{{cite journal | vauthors=Schleh MM, Caslin HI, Hasty AH | title=Metaflammation in obesity and its therapeutic targeting | journal=Science Translational Medicine | volume=15 | issue=723 | pages=eadf9382 | year=2023 | doi = 10.1126/scitranslmed.adf9382 | pmc=10847980 | pmid=37992150 | doi-access=free }} and obesity tends to increase with age. A study of Swedish elderly found that a CD4+/CD8+ ratio less than one was associated with short-term likelihood of death.
Immunological aging is characterized by low proportions of naive CD8+ cells and high numbers of memory CD8+ cells,{{cite journal | author=Turner JE| title=Is immunosenescence influenced by our lifetime "dose" of exercise? | journal=Biogerontology | volume=17 | issue=3 | pages=581–602 | year=2016 | doi = 10.1007/s10522-016-9642-z | pmc=4889625 | pmid=27023222 }}{{cite journal | vauthors=Tibbs TN, Lopez LR, Arthur JC | title=The influence of the microbiota on immune development, chronic inflammation, and cancer in the context of aging | journal=Microbial Cell | volume=6 | issue=8 | pages=324–334 | year=2019 | doi = 10.15698/mic2019.08.685 | doi-broken-date=2024-11-02 | pmc=6685047 | pmid=31403049 }} particularly when cytomegalovirus is present. Exercise can reduce or reverse this effect, when not done at extreme intensity and duration.
Both effector helper T cells (Th1 and Th2) and regulatory T cells (Treg) cells have a CD4 surface marker, such that although total CD4+ T cells decrease with age, the relative percent of CD4+ T cells increases.{{cite journal | vauthors=Jagger A, Shimojima Y, Goronzy JJ, Weyand CM | title=Regulatory T cells and the immune aging process: a mini-review| journal=Gerontology | volume=60 |issue=2 | pages=130–137 | year=2014 | doi = 10.1159/000355303| pmc=4878402 | pmid=24296590}} The increase in Treg with age results in suppressed immune response to infection, vaccination, and cancer, without suppressing the chronic inflammation associated with aging.